JP2007186422A - Arylsulfide derivative - Google Patents

Arylsulfide derivative Download PDF

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Publication number
JP2007186422A
JP2007186422A JP2004019666A JP2004019666A JP2007186422A JP 2007186422 A JP2007186422 A JP 2007186422A JP 2004019666 A JP2004019666 A JP 2004019666A JP 2004019666 A JP2004019666 A JP 2004019666A JP 2007186422 A JP2007186422 A JP 2007186422A
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JP
Japan
Prior art keywords
optionally substituted
compound
sulfanyl
heterocycle
dichloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
JP2004019666A
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Japanese (ja)
Inventor
Hiroshi Inami
寛 井波
Kenichi Kawaguchi
賢一 川口
Koichi Kubota
浩一 窪田
Daisuke Kaga
大輔 加賀
Norio Seki
規夫 関
Hiroki Morio
浩樹 森尾
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Astellas Pharma Inc
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Astellas Pharma Inc
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Filing date
Publication date
Application filed by Astellas Pharma Inc filed Critical Astellas Pharma Inc
Priority to JP2004019666A priority Critical patent/JP2007186422A/en
Priority to PCT/JP2005/001550 priority patent/WO2005073183A1/en
Publication of JP2007186422A publication Critical patent/JP2007186422A/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound which can be used for prophylaxis or treatment of inflammatory diseases and autoimmune diseases which LFA-1 concerns, particularly rheumatoid arthritis, asthma, psoriasis, inflammatory bowel disease, multiple sclerosis, nephritis, etc. <P>SOLUTION: The compound is an aryl sulfide derivative, in which a cyclic group such as piperidine or piperazine is attached to the 4-position via a specific linker such as carbamate, or its salt. The compound is pharmaceutically useful, because the compound has good pharmacological action based on inhibition of the adhesion process of LFA-1 to its ligand ICAM-1. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

本発明は、医薬、特に炎症性疾患又は自己免疫疾患の予防或いは治療剤として有用な、アリールスルフィド誘導体に関する。   The present invention relates to an aryl sulfide derivative useful as a pharmaceutical agent, particularly as a prophylactic or therapeutic agent for inflammatory diseases or autoimmune diseases.

細胞-細胞間接着は、細胞が血管壁等を通過して標的部位へ移行する時や、細胞間でシグナルを伝えあうことで相互に活性化する時に必須の現象である。インテグリンスーパーファミリーはこの接着を介在する重要な分子群の一つであり、細胞膜タンパク質として、細胞-細胞相互作用の場面で重要な役割を果たしている事が知られている。中でもＬＦＡ−１は、白血球全般に発現するインテグリンファミリーの一員として(J. Biol. Chem. 257: 12412-8 (1982))、血管内皮細胞や上皮細胞、線維芽細胞、樹状細胞など多くの細胞でその発現が認められるＩＣＡＭ−１(J. Immunol. 137: 245-254 (1986))、ＩＣＡＭ−２又はＩＣＡＭ−３等の接着を介した多くの生体現象に関わっている。
このＬＦＡ−１とＩＣＡＭ−１間の相互作用は、特にリンパ球のホーミングや炎症部位への炎症性細胞の移動において極めて重要な役割を果たしており(J. Exp. Med. 189: 1467-1478 (1999))、実際これらの分子の発現が関節リウマチ(J. Rheumatol. 24: 458-464 (1997))や喘息(J. Clin. Invest. 94:1840-1845 (1994))、乾癬（Arch. Dermatol. Res. 286: 304-311 (1994)）、多発性硬化症(J. Neuropathol. Exp. Neurol. 55:1060-1072 (1996))等の病変部位で高発現していることが知られている。又、これまでに関節炎や喘息、皮膚炎、腎炎、移植等の動物疾患モデルにおいて、ＬＦＡ−１抗体(Cell. Immunol. 142: 324-337 (1992)、Am. J. Respir. Crit. Care. Med. 153:521-519 (1996)、Transpl. Int. 9: 420-425 (1996))、ＩＣＡＭ−１抗体(Clin. Exp. Immunol. 117: 462-468 (1999) J. Immunol. 150:1074-1083 (1993))、又はＩＣＡＭ−１アンチセンスの有効性が示されている。又、ノックアウトマウス(J. Immunol. 157: 3153-3158 (1996)、Proc. Natl. Acad. Sci. USA 90: 8529-8533 (1993))等を用いた検討からも、ＬＦＡ−１とＩＣＡＭ−１間の相互作用の関与が証明されている。
更に、臨床においてもＬＦＡ−１又はＩＣＡＭ−１を標的とした抗体又はアンチセンスによる治験が、乾癬や炎症性腸疾患他を適応として進められている（N. Engl. J. Med. 349: 2004-2013 (2003)、Gut 51: 30-36 (2002)、J. Allergy Clin. Immunol. 112: 331-338 (2003)）。
以上のことから、ＬＦＡ−１及びＩＣＡＭ−１間の結合を阻害することにより、関節リウマチ、喘息、乾癬、炎症性腸疾患、多発性硬化症又は腎炎などの自己免疫疾患或いは炎症性疾患の病態を改善できると考えられる。 Cell-cell adhesion is an indispensable phenomenon when cells pass through a blood vessel wall or the like and move to a target site, or when they are mutually activated by transmitting signals between cells. The integrin superfamily is one of the important molecular groups that mediate this adhesion and is known to play an important role in cell-cell interaction as a cell membrane protein. Among them, LFA-1 is a member of the integrin family that is expressed in general leukocytes (J. Biol. Chem. 257: 12412-8 (1982)), and has many vascular endothelial cells, epithelial cells, fibroblasts, dendritic cells, etc. It is involved in many biological phenomena through adhesion such as ICAM-1 (J. Immunol. 137: 245-254 (1986)), ICAM-2 or ICAM-3 whose expression is observed in cells.
This interaction between LFA-1 and ICAM-1 plays an extremely important role particularly in homing of lymphocytes and migration of inflammatory cells to the inflammatory site (J. Exp. Med. 189: 1467-1478 ( 1999)), in fact, these molecules are expressed in rheumatoid arthritis (J. Rheumatol. 24: 458-464 (1997)), asthma (J. Clin. Invest. 94: 1840-1845 (1994)), psoriasis (Arch. Dermatol. Res. 286: 304-311 (1994)) and multiple sclerosis (J. Neuropathol. Exp. Neurol. 55: 1060-1072 (1996)) are known to be highly expressed. ing. Furthermore, in animal disease models such as arthritis, asthma, dermatitis, nephritis, transplantation, etc., LFA-1 antibody (Cell. Immunol. 142: 324-337 (1992), Am. J. Respir. Crit. Care. Med. 153: 521-519 (1996), Transpl. Int. 9: 420-425 (1996)), ICAM-1 antibody (Clin. Exp. Immunol. 117: 462-468 (1999) J. Immunol. 150: 1074-1083 (1993)), or the effectiveness of ICAM-1 antisense. In addition, from studies using knockout mice (J. Immunol. 157: 3153-3158 (1996), Proc. Natl. Acad. Sci. USA 90: 8529-8533 (1993)), etc., LFA-1 and ICAM- The involvement of interactions between 1 has been proven.
Furthermore, clinical trials using antibodies or antisense targeting LFA-1 or ICAM-1 are also being promoted in the clinic for indications of psoriasis, inflammatory bowel disease, etc. (N. Engl. J. Med. 349: 2004). -2013 (2003), Gut 51: 30-36 (2002), J. Allergy Clin. Immunol. 112: 331-338 (2003)).
From the above, by inhibiting the binding between LFA-1 and ICAM-1, the pathological condition of autoimmune diseases or inflammatory diseases such as rheumatoid arthritis, asthma, psoriasis, inflammatory bowel disease, multiple sclerosis or nephritis Can be improved.

特許文献１及び特許文献２には、下記一般式で示される桂皮酸アミド誘導体等が、ＬＦＡ−１とＩＣＡＭ−１との結合を阻害し、炎症及び免疫疾患の治療に用いられることが報告されている。

Figure 2007186422
（式中、Arは-H、ハロゲン及びアルキル等から選択された基で置換された、アリール又はヘテロアリール等を、R1、R2、R3、R4及びR5は独立して、-H、ハロゲン又はアルキル等を示す。但し、R1或いはR3の少なくとも一方は下記に示される基である。
Figure 2007186422
 ここで、R8及びR9は-H又はアルキル等を、R10及びR11は-H、アルキル、置換されていてもよいヘテロシクリル等、又はNR10R11として置換されていてもよいヘテロシクリルを示す。詳細は当該公報参照。）
これらの化合物は、いずれも桂皮酸アミド構造を有することが特徴であり、本発明化合物とは構造が異なる。 Patent Literature 1 and Patent Literature 2 report that cinnamic acid amide derivatives represented by the following general formula inhibit the binding between LFA-1 and ICAM-1 and are used for the treatment of inflammation and immune diseases. ing.
Figure 2007186422
 (Wherein Ar represents aryl or heteroaryl substituted with a group selected from -H, halogen, alkyl, etc., R 1 , R 2 , R 3 , R 4 and R 5 are independently- H, halogen, alkyl, etc., provided that at least one of R 1 or R 3 is a group shown below.
Figure 2007186422
 Here, R 8 and R 9 are -H or alkyl, R 10 and R 11 are -H, alkyl, an optionally substituted heterocyclyl, etc., or an optionally substituted heterocyclyl as NR 10 R 11 Show. See the official gazette for details. )
These compounds are all characterized by having a cinnamic acid amide structure, and are different in structure from the compound of the present invention.

国際公開第00/39081号パンフレットInternational Publication No. 00/39081 Pamphlet 国際公開第00/59880号パンフレットInternational Publication No. 00/59880 Pamphlet

ＬＦＡ−１とそのリガンドであるＩＣＡＭ−１との結合を阻害する化合物は、炎症性疾患及び自己免疫疾患、殊に関節リウマチ、喘息、乾癬、炎症性腸疾患、多発性硬化症又は腎炎等の予防或いは治療に有用と考えられるが、現在までに臨床で効果が確認された低分子化合物の報告はない。 Compounds that inhibit the binding of LFA-1 to its ligand ICAM-1 are inflammatory diseases and autoimmune diseases, particularly rheumatoid arthritis, asthma, psoriasis, inflammatory bowel disease, multiple sclerosis or nephritis, etc. Although it is considered useful for prevention or treatment, there has been no report of a low molecular weight compound that has been confirmed to be effective clinically so far.

本発明者等は、ＬＦＡ−１とＩＣＡＭ−１との結合阻害作用を有する化合物につき鋭意検討した結果、下記一般式（I）に示すように、ベンゼン環の4位にカルバマート等の特定のリンカーを介して特定の環基、特に好ましくはピペリジン若しくはピペラジン等の環基が結合した構造に特徴を有する新規なアリールスルフィド誘導体が、ＬＦＡ−１とＩＣＡＭ−１との結合阻害作用に基づく良好な薬理作用を有することを確認し、これを有効成分とする医薬組成物が、炎症性疾患及び自己免疫疾患の治療及び予防剤となりうることを知見して本発明を完成したものである。
即ち、本発明は下記一般式（I）で示される新規なアリールスルフィド誘導体又はその製薬学的に許容される塩に関する。 As a result of intensive studies on a compound having an inhibitory action on the binding between LFA-1 and ICAM-1, the present inventors, as shown in the following general formula (I), a specific linker such as carbamate at the 4-position of the benzene ring A novel aryl sulfide derivative characterized by a structure in which a specific ring group, particularly preferably a ring group such as piperidine or piperazine, is bonded through a pharmacologically favorable pharmacology based on the binding inhibitory action between LFA-1 and ICAM-1 The present invention has been completed by confirming that it has an action and discovering that a pharmaceutical composition containing this as an active ingredient can be a therapeutic and preventive agent for inflammatory diseases and autoimmune diseases.
That is, the present invention relates to a novel aryl sulfide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

Figure 2007186422
（式中の記号は以下の意味を示す。
A：アリール又はヘテロ環基；
R1：同一又は互いに異なって、-H、-R0、ハロゲン、-OH、-O-R0、-O-CO-NR4-R0、-NH2、-NO2、-NR4-R0、-S-R0、-SO-R0、-SO2-R0、-CO-R0、-CHO、-CN、-CO-NH2、-CO-NR4-R0、-CO2H、-CO2-R0、-CO-NH-OH、-SO3H、-SO2-NH2、-SO2-NR4-R0、-NR4-CO-R0、-NR4-SO2-R0、置換されていてもよいシクロアルキル、-低級アルケニレン-CO2-R0、-低級アルケニレン-CO2H、-低級アルケニレン-CO-NH2、-低級アルケニレン-CO-NR4-R0、-低級アルケニレン-CO-置換されていてもよいヘテロ環、置換されていてもよいヘテロ環、-CO-置換されてもよいヘテロ環、-O-置換されてもよいヘテロ環、-NR4-置換されてもよいヘテロ環、-NR4-CO-置換されてもよいヘテロ環、-CO-NR4-置換されてもよいヘテロ環、-S-置換されてもよいヘテロ環、-NR4-SO2-置換されてもよいヘテロ環、置換されていてもよいアリール、-CO-置換されてもよいアリール、-O-置換されてもよいアリール、-NR4-置換されてもよいアリール、-NR4-CO-置換されてもよいアリール、-CO-NR4-置換されてもよいアリール、-S-置換されてもよいアリール又は-NR4-SO2-置換されてもよいアリール；
R0：同一若しくは互いに異なって、置換されていてもよい低級アルキル；
R4：同一若しくは互いに異なって、-H又は置換されていてもよい低級アルキル；
R00：同一若しくは互いに異なって、-OH又は-O-低級アルキルで置換されていてもよい低級アルキレン；
n：1、2又は3；
R2及びR3：同一又は互いに異なって、-H、-R0、ハロゲン、-CN、-NO2、-O-R0、-S-R0、-SO-R0又は-SO2-R0、但しR2及びR3が同時に-Hではない；
X：-R00-、低級アルケニレン、-R00-O-CO-、-R00-O-CO-NR4-、-R00-O-CO-NR4-R00-、-R00-CO-、低級アルケニレン-NR4-、低級アルケニレン-NR4-R00-又は低級アルケニレン-NR4-CO-；
B：置換されていてもよいアリール、置換されていてもよいシクロアルキル、又は置換されていてもよいヘテロ環基；
Y：単結合、-R00-、-CO-R00-、-NR4-R00-、-O-R00-、-CO2-R00-、-CO-NR4-R00-、-NR4-CO-R00-又は-R00-O-R00-；及び
Z：-H、-R0、-CO2H、-CO-NH2、-CO2-R0、-CHO、-CO-NH-OH、-C(NH)-NH2、-SO3H、-SO2-R0、-SO2-NH2、-SO2-NR4-R0 、-PO(OR4)2、-O-PO(OR4)2、-CN、-OH、-O-R0、-NH2、-NR4-R0、-NH-C(NH)-NH2、-NR4-CO-R0、-NR4-SO2-R0、-NR4-CO-NH2、-NR4-CO-NR4-R0、-NR4-CO-NR4-R0、-NR4-SO2-NH2、-O-CO-NR4-R0、-CO-NR4-R0、-CO-R0、-O-CO-R0、-CO-CO2H、置換されていてもよいヘテロ環、置換されていてもよいアリール、置換されていてもよいシクロアルキル、-CO-置換されていてもよいヘテロ環、-CO-置換されていてもよいアリール、-CO-NR4-置換されていてもよいヘテロ環、-CO-NR4-置換されていてもよいアリール、-CO-O-置換されていてもよいヘテロ環、-SO2-置換されていてもよいヘテロ環、-O-CO-置換されていてもよいヘテロ環、-O-置換されていてもよいヘテロ環、-NR4-置換されていてもよいヘテロ環、-NR4-CO-置換されていてもよいヘテロ環、-NR4-SO2-置換されていてもよいヘテロ環及び-SO2-NR4-置換されていてもよいヘテロ環。以下同様。）
Figure 2007186422
 (The symbols in the formula have the following meanings.
A: an aryl or heterocyclic group;
R 1 : same or different, —H, —R 0 , halogen, —OH, —OR 0 , —O—CO—NR 4 —R 0 , —NH 2 , —NO 2 , —NR 4 —R 0 , -SR 0 , -SO-R 0 , -SO 2 -R 0 , -CO-R 0 , -CHO, -CN, -CO-NH 2 , -CO-NR 4 -R 0 , -CO 2 H, -CO 2 -R 0 , -CO-NH-OH, -SO 3 H, -SO 2 -NH 2 , -SO 2 -NR 4 -R 0 , -NR 4 -CO-R 0 , -NR 4 -SO 2 -R 0, optionally substituted cycloalkyl, - lower alkenylene -CO 2 -R 0, - lower alkenylene -CO 2 H, - lower alkenylene -CO-NH 2, - lower alkenylene -CO-NR 4 - R 0 , -lower alkenylene-CO-optionally substituted heterocycle, optionally substituted heterocycle, -CO-optionally substituted heterocycle, -O-optionally substituted heterocycle,- NR 4 -optionally substituted heterocycle, -NR 4 -CO-optionally substituted heterocycle, -CO-NR 4 -optionally substituted heterocycle, -S-optionally substituted heterocycle, -NR 4 -SO 2 -optionally substituted heterocycle, substituted Is aryl which may have, -CO- optionally substituted aryl, -O- optionally substituted aryl, -NR 4 - optionally substituted aryl, which may be -NR 4 -CO- substituted aryl , -CO-NR 4 - optionally substituted aryl, -S- optionally substituted aryl or -NR be 4 -SO 2 - optionally substituted aryl;
R 0 : the same or different from each other and optionally substituted lower alkyl;
R 4 : the same or different from each other, —H or optionally substituted lower alkyl;
R 00 : lower alkylene which may be the same or different and may be substituted with —OH or —O-lower alkyl;
n: 1, 2 or 3;
R 2 and R 3 are the same or different from each other, -H, -R 0 , halogen, -CN, -NO 2 , -OR 0 , -SR 0 , -SO-R 0 or -SO 2 -R 0 , R 2 and R 3 are not simultaneously -H;
X: -R 00 -, lower alkenylene, -R 00 -O-CO -, - R 00 -O-CO-NR 4 -, - R 00 -O-CO-NR 4 -R 00 -, - R 00 - CO-, lower alkenylene -NR 4 -, lower alkenylene -NR 4 -R 00 - or lower alkenylene -NR 4 -CO-;
B: aryl which may be substituted, cycloalkyl which may be substituted, or heterocyclic group which may be substituted;
Y: Single bond, -R 00- , -CO-R 00- , -NR 4 -R 00- , -OR 00- , -CO 2 -R 00- , -CO-NR 4 -R 00- , -NR 4 -CO-R 00 -or -R 00 -OR 00- ; and
Z: -H, -R 0 , -CO 2 H, -CO-NH 2 , -CO 2 -R 0 , -CHO, -CO-NH-OH, -C (NH) -NH 2 , -SO 3 H , -SO 2 -R 0 , -SO 2 -NH 2 , -SO 2 -NR 4 -R 0 , -PO (OR 4 ) 2, -O-PO (OR 4 ) 2 , -CN, -OH,- OR 0 , -NH 2 , -NR 4 -R 0 , -NH-C (NH) -NH 2 , -NR 4 -CO-R 0 , -NR 4 -SO 2 -R 0 , -NR 4 -CO- NH 2 , -NR 4 -CO-NR 4 -R 0 , -NR 4 -CO-NR 4 -R 0 , -NR 4 -SO 2 -NH 2 , -O-CO-NR 4 -R 0 , -CO -NR 4 -R 0 , -CO-R 0 , -O-CO-R 0 , -CO-CO 2 H, optionally substituted heterocycle, optionally substituted aryl, optionally substituted Good cycloalkyl, -CO-optionally substituted heterocycle, -CO-optionally substituted aryl, -CO-NR 4 -optionally substituted heterocycle, -CO-NR 4 -substituted Optionally substituted aryl, —CO—O—optionally substituted heterocycle, —SO 2 —optionally substituted heterocycle, —O—CO—optionally substituted heterocycle, —O— heterocycle which may be substituted, -NR 4 - Conversion which may be heterocyclic, -NR 4 -CO- optionally substituted heterocycle, -NR 4 -SO 2 - optionally substituted heterocyclic and -SO 2 -NR 4 - substituted An optional heterocycle. The same applies below. )

本発明化合物はＬＦＡ−１／ＩＣＡＭ−１結合阻害活性を有しており、炎症性疾患又は自己免疫疾患、特に、運動器系疾患（関節リウマチ等）、消化器系疾患（潰瘍性大腸炎、クローン病等）、皮膚炎症性疾患（アトピー性皮膚炎、乾癬等）、全身性エリテマトーデス、シェーグレン症候群、腎炎、呼吸器疾患（喘息、成人呼吸切迫症候群等）、中枢疾患（脳卒中、多発性硬化症等）、移植拒絶（GVH病等）、心血管疾患（心筋組織の再灌流阻害、血栓症、血栓溶解後の再閉塞、動脈硬化症等）等の予防又は治療に有用である。   The compounds of the present invention have LFA-1 / ICAM-1 binding inhibitory activity, and are inflammatory diseases or autoimmune diseases, in particular, musculoskeletal diseases (such as rheumatoid arthritis), gastrointestinal diseases (ulcerative colitis, Crohn's disease, etc.), skin inflammatory diseases (atopic dermatitis, psoriasis, etc.), systemic lupus erythematosus, Sjogren's syndrome, nephritis, respiratory diseases (eg, asthma, adult respiratory urge syndrome), central diseases (stroke, multiple sclerosis) Etc.), transplant rejection (GVH disease, etc.), cardiovascular disease (reperfusion inhibition of myocardial tissue, thrombosis, reocclusion after thrombolysis, arteriosclerosis, etc.) and the like.

以下、本発明について詳述する。
本明細書中、「アルキル」、「アルキレン」及び「アルケニレン」は直鎖状又は分枝状の炭化水素基を示す。「低級アルキル」とは炭素数１〜６の（以後C1-6と略）アルキルであり、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、t-ブチル、ペンチル、イソペンチル、ネオペンチル、へキシル等が挙げられる。好ましくはC1-4アルキルであり、更に好ましくは、メチル、エチル及びイソプロピルである。「低級アルキレン」とはC1-6アルキレンであり、メチレン、エチレン、プロピレン、メチルメチレン、トリメチレン、テトラメチレン、ペンタメチレン、ヘキサメチレン等が挙げられる。好ましくはC1-4アルキレン、更に好ましくはメチレン及びエチレンである。「低級アルケニレン」とはC2-6のアルキレンの任意の位置に１個以上の二重結合を有する基であり、ビニレン、プロペニレン、ブテニレン、ペンテニレン、ヘキセニレン等が挙げられる。好ましくはC2-4のアルケニレンである。
「ハロゲン」とは、Ｆ、Ｃｌ、Ｂｒ又はＩを示す。「ハロゲンで置換された低級アルキル」とは、１個以上のハロゲンで置換された低級アルキルであり、好ましくは、１〜５個のFを有するC1-2のアルキルであり、より好ましくはフルオロメチル、ジフルオロメチル、トリフルオロメチル、トリフルオロエチルが挙げられる。
「アリール」とは、C6-14の単環〜三環式芳香族炭化水素環基であり、好ましくはフェニル及びナフチルである。又、二若しくは三環式アリールの一つの環が水素化されたものも包含され、例えばテトラヒドロナフチル等が挙げられる。
「シクロアルキル」とは、C3-10の環状の飽和炭化水素環基であり、架橋を有していてもよい。好ましくはシクロペンチル、シクロヘキシル、シクロヘプチル及びアダマンチルである。
「ヘテロ環」とは、O、S及びNから選択されるヘテロ原子を１〜４個含有する単環３〜８員、好ましくは５〜７員環基であり、不飽和環であるヘテロアリール、飽和環であるヘテロシクロアルキル、及び前記ヘテロアリールが部分的に水素化された環基を含む。当該ヘテロ環同士、又はベンゼン環とヘテロ環が縮環し二〜三環式ヘテロ環を形成してもよい。環原子であるS又はNが酸化されオキシドやジオキシドを形成してもよい。ヘテロアリールとして好ましくは、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、イミダゾリル、ピロリル、ピロリジル、トリアゾリル、テトラゾリル、チエニル、フリル、チアゾリル、ピラゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、チアジアゾリル、オキサジアゾリル、インドリル、ベンゾイミダゾリル、キナゾリル、キノキサリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、及びクロマニル等が挙げられる。ヘテロシクロアルキル基、又はヘテロアリール基が部分的に水素化された環基として好ましくは、テトラヒドロキノリル、テトラヒドロイソキノリル、ピペリジル、ピペラジニル、アゼパニル、ジアゼパニル、テトラヒドロフラニル、テトラヒドロピラニル、モルホリニル、インドリニル、テトラヒドロベンゾイミダゾリル、ジヒドロベンゾジオキシニル及びジヒドロベンズイミダゾリジニル等が挙げられる。ヘテロシクロアルキル、及びヘテロアリールが部分的に水素化された環基においては、任意の炭素原子がオキソ基で置換されていてもよい。又、上記ヘテロ環は、スピロ環及び架橋されたヘテロ環を包含する。当該スピロ環としては、2,8-ジアザスピロ[4.5]デカン-1-オン-8-イル、1,3,8-トリアザスピロ[4.5]デカン-2,4-ジオン-8-イル等が挙げられる。又、当該架橋環としては、2,5-ジアザビシクロ[2.2.1]ヘプタン-2-イル、8-アザビシクロ[3.2.1]オクタン-3-イル等が挙げられる。
本明細書において「アリール」、「シクロアルキル」及び「ヘテロ環」は便宜上一価基として記載してあるが、構造によっては二価基以上の多価基である場合がある。本発明はそれらの構造を包含する。例えば二価基の具体的な態様としては、有機化合物命名法に従って上記環基の接尾辞をジイルに変換したものが対応する。例えばピペリジンジイル等については、1,4-ピペリジンジイル、1,3-ピペリジンジイルに加え4,4,-ピペリジンジイル等のジェミナル置換形式であるものも包含する。
「置換されていてもよい」とは、「無置換であること」或いは「置換基を有していること」のいずれかを示す。
例えば、「置換されていてもよい低級アルキル」及び「置換されていてもよい低級アルキレン」において、これらの低級アルキル及び低級アルキレンは１〜５個の置換基を有していてもよい。置換基として好ましくは下記G群に示す基であり、特に好ましくは、-ハロゲン、-OH、-CO2H、及び-O-C1-6アルキルである。
G群： -ハロゲン、-シクロアルキル、-ヘテロ環、-アリール、-OH、-O-C1-6アルキル、-O-ハロゲンで置換されたC1-6アルキル、-S-C1-6アルキル、-SO2-C1-6アルキル、-O-アリール、-O-シクロアルキル、-O-ヘテロ環、-S-シクロアルキル、-S-ヘテロ環、-NH-アリール、-N(C1-6アルキル)-アリール、-NH-シクロアルキル、-N(C1-6アルキル)-シクロアルキル、-NH-ヘテロ環、-N(C1-6アルキル)-ヘテロ環、-NH2、-NH-C1-6アルキル、-N(C1-6アルキル)2、-CO-C1-6アルキル、-CO-NH-C1-6アルキル、-NH-CO-C1-6アルキル、-N(C1-6アルキル)-CO-C1-6アルキル、-CO-N(C1-6アルキル)2、-CO2-C1-6アルキル、-SO2-NH-C1-6アルキル、-SO2-N(C1-6アルキル)2、-NH-SO2-C1-6アルキル、-N(C1-6アルキル)-SO2-C1-6アルキル、-NH-CO2-C1-6アルキル、-N(C1-6アルキル)-CO2-C1-6アルキル、-O-CO-NH-C1-6アルキル、-O-CO-N(C1-6アルキル)2、-CO-NH2、-CO2H、-SO3H、-SO2-NH2、-NH-CO-NH2、-N(C1-6アルキル)-CO-NH2、-NH-CO-NH(C1-6アルキル)、N(C1-6アルキル)-CO-NH(C1-6アルキル)、-N(C1-6アルキル)-CO-N(C1-6アルキル)2、-C(NH)-NH2、-NH-C(NH)-NH2、-O-C1-6アルキレン-CO2H、-O-C1-6アルキレン-OH、-NH-C1-6アルキレン-OH、-NH-C1-6アルキレン-CO2H、-CO2-C1-6アルキレン-OH、-CO2-C1-6アルキレン-CO2H、-NO2及び-CN。ここに当該ヘテロ環及びアリールは、ハロゲン、OH及びC1-4アルキルから選択される1〜5個の置換基で置換されていてもよい。
又、「置換されていてもよいアリール」、「置換されていてもよいシクロアルキル」及び「置換されていてもよいヘテロ環」において、これらの環基は１〜５個の範囲内で置換基を有していてもよく、置換基として好ましくは、前記G群から選択される基で置換されていてもよい低級アルキル、及び前記G群に示される基である。
「ヘテロ原子で中断されていてもよい低級アルキレン」とは、低級アルキレン、或いは低級アルキレンの途中又は末端にO、S(O)p（p=0、1又は2）及びNR7（R7はH又はC1-6アルキル）から選択されるヘテロ原子1個又は2個が挿入された基を表す。例えば、-CH2CH2-、-O-CH2CH2-、-CH2-O-CH2-、-O-CH2CH2-O-、-CH2-S-CH2-、-CH2-S(O)-CH2-、-CH2-N(CH3)-CH2-等の基が挙げられ、好ましくは-CH2CH2-である。又、該ヘテロ原子が窒素原子の場合、隣接位がオキソ化されていてもよく、例えば-CH2-CO-NH-CH2-等が挙げられる。 Hereinafter, the present invention will be described in detail.
In the present specification, “alkyl”, “alkylene” and “alkenylene” represent a linear or branched hydrocarbon group. “Lower alkyl” means alkyl having 1 to 6 carbon atoms (hereinafter abbreviated as C 1-6 ), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc. Is mentioned. C 1-4 alkyl is preferable, and methyl, ethyl and isopropyl are more preferable. “Lower alkylene” is C 1-6 alkylene and includes methylene, ethylene, propylene, methylmethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. C 1-4 alkylene is preferable, and methylene and ethylene are more preferable. “Lower alkenylene” is a group having one or more double bonds at any position of C 2-6 alkylene, and examples thereof include vinylene, propenylene, butenylene, pentenylene, hexenylene and the like. C 2-4 alkenylene is preferred.
“Halogen” refers to F, Cl, Br or I. “Lower alkyl substituted with halogen” is lower alkyl substituted with one or more halogens, preferably C 1-2 alkyl having 1 to 5 F, more preferably fluoro. Examples include methyl, difluoromethyl, trifluoromethyl, and trifluoroethyl.
“Aryl” is a C 6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, preferably phenyl and naphthyl. Moreover, the thing by which one ring of bi- or tricyclic aryl was hydrogenated is also included, for example, tetrahydronaphthyl etc. are mentioned.
“Cycloalkyl” is a C 3-10 cyclic saturated hydrocarbon ring group which may have a bridge. Cyclopentyl, cyclohexyl, cycloheptyl and adamantyl are preferred.
“Heterocycle” is a monocyclic 3 to 8 membered, preferably 5 to 7 membered cyclic group containing 1 to 4 heteroatoms selected from O, S and N, and is a heteroaryl which is an unsaturated ring , A saturated heterocycloalkyl, and a ring group in which the heteroaryl is partially hydrogenated. The heterocycles or the benzene ring and the heterocycle may be condensed to form a bi to tricyclic heterocycle. The ring atom S or N may be oxidized to form an oxide or a dioxide. Heteroaryl is preferably pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidyl, triazolyl, tetrazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indolyl, benzimidazolyl, quinazolyl, quinoxalyl, Examples include quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, and chromanyl. A ring group in which a heterocycloalkyl group or a heteroaryl group is partially hydrogenated is preferably tetrahydroquinolyl, tetrahydroisoquinolyl, piperidyl, piperazinyl, azepanyl, diazepanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, indolinyl , Tetrahydrobenzimidazolyl, dihydrobenzodioxinyl and dihydrobenzimidazolidinyl. In the cyclic group in which heterocycloalkyl and heteroaryl are partially hydrogenated, any carbon atom may be substituted with an oxo group. The heterocycle includes a spiro ring and a bridged heterocycle. Examples of the spiro ring include 2,8-diazaspiro [4.5] decan-1-one-8-yl, 1,3,8-triazaspiro [4.5] decan-2,4-dione-8-yl and the like. Examples of the bridged ring include 2,5-diazabicyclo [2.2.1] heptan-2-yl, 8-azabicyclo [3.2.1] octan-3-yl and the like.
In the present specification, “aryl”, “cycloalkyl” and “heterocycle” are described as monovalent groups for the sake of convenience. However, depending on the structure, they may be divalent or more polyvalent groups. The present invention encompasses these structures. For example, a specific embodiment of the divalent group corresponds to one obtained by converting the above-mentioned ring group suffix to diyl according to the organic compound nomenclature. For example, piperidinediyl and the like include geminal substitution forms such as 1,4-piperidinediyl, 1,3-piperidinediyl, and 4,4, -piperidinediyl.
The term “which may be substituted” means either “unsubstituted” or “having a substituent”.
For example, in “optionally substituted lower alkyl” and “optionally substituted lower alkylene”, these lower alkyl and lower alkylene may have 1 to 5 substituents. The substituent is preferably a group shown in the following group G, and particularly preferably —halogen, —OH, —CO 2 H, and —OC 1-6 alkyl.
Group G: -halogen, -cycloalkyl, -heterocycle, -aryl, -OH, -OC 1-6 alkyl, C 1-6 alkyl substituted with -O-halogen, -SC 1-6 alkyl, -SO 2 -C 1-6 alkyl, -O-aryl, -O-cycloalkyl, -O-heterocycle, -S-cycloalkyl, -S-heterocycle, -NH-aryl, -N (C 1-6 alkyl ) -Aryl, -NH-cycloalkyl, -N (C 1-6 alkyl) -cycloalkyl, -NH-heterocycle, -N (C 1-6 alkyl) -heterocycle, -NH 2 , -NH-C 1-6 alkyl, -N (C 1-6 alkyl) 2 , -CO-C 1-6 alkyl, -CO-NH-C 1-6 alkyl, -NH-CO-C 1-6 alkyl, -N ( C 1-6 alkyl) -CO-C 1-6 alkyl, -CO-N (C 1-6 alkyl) 2 , -CO 2 -C 1-6 alkyl, -SO 2 -NH-C 1-6 alkyl, -SO 2 -N (C 1-6 alkyl) 2 , -NH-SO 2 -C 1-6 alkyl, -N (C 1-6 alkyl) -SO 2 -C 1-6 alkyl, -NH-CO 2 -C 1-6 alkyl, -N (C 1-6 alkyl) -CO 2 -C 1-6 alkyl, -O-CO-NH-C 1-6 alkyl, -O-CO-N (C 1-6 alkyl) 2 , -CO-NH 2 , -CO 2 H, -SO 3 H, -SO 2 -NH 2 , -NH-CO-NH 2 , -N (C 1-6 alkyl)- CO-NH 2 , -NH-CO-NH (C 1-6 alkyl), N (C 1-6 alkyl) -CO-NH (C 1-6 alkyl), -N (C 1-6 alkyl) -CO -N (C 1-6 alkyl) 2 , -C (NH) -NH 2 , -NH-C (NH) -NH 2 , -OC 1-6 alkylene-CO 2 H, -OC 1-6 alkylene-OH , -NH-C 1-6 alkylene-OH, -NH-C 1-6 alkylene-CO 2 H, -CO 2 -C 1-6 alkylene-OH, -CO 2 -C 1-6 alkylene-CO 2 H , -NO 2 and -CN. Here, the heterocycle and aryl may be substituted with 1 to 5 substituents selected from halogen, OH and C 1-4 alkyl.
In the “optionally substituted aryl”, “optionally substituted cycloalkyl” and “optionally substituted heterocycle”, these ring groups may be substituted within the range of 1 to 5 The substituent is preferably a lower alkyl which may be substituted with a group selected from Group G, and a group shown in Group G.
“Lower alkylene optionally interrupted by heteroatoms” means lower alkylene, or O, S (O) p (p = 0, 1 or 2) and NR 7 (R 7 is the middle or the terminal of lower alkylene) H or C 1-6 alkyl) represents a group in which one or two heteroatoms selected from: For example, -CH 2 CH 2 -, - O-CH 2 CH 2 -, - CH 2 -O-CH 2 -, - O-CH 2 CH 2 -O -, - CH 2 -S-CH 2 -, - CH 2 -S (O) -CH 2 -, - CH 2 -N (CH 3) -CH 2 - groups such as the like, preferably -CH 2 CH 2 -. When the heteroatom is a nitrogen atom, the adjacent position may be oxoated, and examples thereof include —CH 2 —CO—NH—CH 2 —.

本発明化合物（Ｉ）における好ましい化合物は以下の化合物である：
(1) Xが低級アルケニレン、-R00-O-CO-、-R00-O-CO-NR4-又は-R00-O-CO-NR4-R00-；
R1が同一又は互いに異なって、-H、-R0、ハロゲン、-O-R0、-NR4-CO-R0、置換されていてもよいヘテロ環、又は-R00-置換されていてもよいヘテロ環；
R2及びR3が同一又は互いに異なって、-H、低級アルキル、ハロゲン、-NO2、-CN、又はハロゲンで置換された低級アルキル、但しR2及びR3が同時に-Hではない；及び
Bがフェニレン、テトラヒドロピランジイル又は下式(i)〜(iv)から選択される基

Figure 2007186422
（ここにk：0、1又は2；
ｑ：0、1又は2；
m：1又は2；
R5及びR6：同一又は互いに異なって、-H又は低級アルキル、或いはR5及びR6が一体となってオキソ基を形成してもよく、或いはR5及びR6が一体となってヘテロ原子で中断されていてもよい低級アルキレンとして、Ｂが架橋環又はスピロ環を形成してもよい）；
である化合物。
(2) Aが、ベンゼン環と単環式へテロ環が縮合した二環式ヘテロ環基、又はフェニル、より好ましくは、単環５〜６員のヘテロ環が縮合したフェニル、又はフェニルである化合物。
(3) Xが、低級アルケニレン、-R00-O-CO-、-R00-O-CO-NR4-又は-R00-O-CO-NR4-R00-である化合物。特に、Bが前記式(i)若しくは(iv)で示される基の場合、Xが低級アルケニレン又は-R00-O-CO-である化合物がより好ましく、更に好ましくはC3-5のアルケニレン又は-R00-O-CO-、より更に好ましくはプロピレン又は-R00-O-CO-、特に好ましくは(E)-CH=CH-CH2-又は-CH2-O-CO-で示される化合物である。又一方、Ｂが前記式(ii)若しくは(iii)で示される基、又はフェニレン若しくはテトラヒドロピランジイルの場合、Xが低級アルケニレン、-R00-O-CO-NR4-又は-R00-O-CO-NR4-R00-である化合物がより好ましく、更に好ましくは-R00-O-CO-NR4-又は-R00-O-CO-NR4-R00-で示される化合物である。ここにR00としてはC1-3アルキレン、特にメチレンが好ましく、又、R4としては-H又はメチルが好ましい。
(4) R1が同一又は互いに異なって、-H、-R0、ハロゲン、-O-R0、-R00-OH、-R00-NR4-R0、置換されていてもよいヘテロ環、又は-R00-置換されていてもよいヘテロ環である化合物。より好ましくは-R0、ハロゲン、-O-R0、-R00-OH、-R00-NR4-R0、置換されていてもよいヘテロ環、又は-R00-置換されていてもよいヘテロ環である化合物。ここにR00としてはC1-3アルキレンが、R4としては-H又はメチルが、ヘテロ環としては単環５〜６員のヘテロ環基がそれぞれ好ましい。又、「置換されていてもよいヘテロ環」及び「置換されていてもよいアリール」における好ましい置換基は、特に-CO2H、-CO2-C1-4アルキル及びメチルである。
(5) nが1又は2である化合物。
(6) R2及びR3が同一又は互いに異なって、-H、ハロゲン、-CN、-NO2又はハロゲンで置換された低級アルキルである化合物。より好ましくは-Cl、-NO2又はトリフルオロメチル基である化合物。
(7) Bがフェニレン、ピペリジンジイル、ピペラジンジイル、テトラヒドロピランジイル、モルホリンジイル、ピロリジンジイル、ホモピペラジンジイル又は8-アザビシクロ[3.2.1]オクタンジイルである化合物。より好ましくはフェニレン、ピロリジンジイル、ピペリジンジイル又はピペラジンジイルである化合物。
(8) Yが、単結合、-R00-、-CO-R00-、-NR4-R00-、-O-R00-、-CO2-R00-、-CO-NR4-R00-、-NR4-CO-R00-又は-R00-O-R00-である化合物。特に、Bが前記式(i)若しくは(ii)で示される基、又はフェニレン若しくはテトラヒドロピランジイルの場合、Yが単結合、-R00-、-NR4-R00-、-O-R00-、-CO-NR4-R00-又は-NR4-CO-R00-である化合物がより好ましい。又一方、Bが前記式(iii)若しくは(iv)で示される基の場合、Yが単結合、-R00-、-CO-R00-、-CO2-R00-、-CO-NR4-R00-又は-R00-O-R00-である化合物がより好ましい。ここにR00としてはC1-3アルキレンが好ましく、R4としては-H又はメチルが好ましい。
(9) Zが-H、-R0、置換されていてもよいヘテロ環、-CO2H、-CO-NH2、-OH、-SO2-R0、-NR4-R0、-NR4-CO-R0、-NR4-SO2-R0、-CO-NR4-R0、-CO-R0又は-CO-置換されていてもよいヘテロ環である化合物。ここにR0としてはC1-3アルキル、特にメチルが好ましく、R4としては、-H又はメチルが好ましい。又、ヘテロ環としては単環５〜６員のヘテロ環が好ましく、更に好ましくはテトラヒドロフリル、ピペリジニル、ピペラジニル、モルホリニル、イミダゾリル、ピリジニル環である。ここで、「置換されていてもよいヘテロ環」及び「置換されていてもよいアリール」における好ましい置換基は、-C1-4アルキル、-C1-4アルキレン-OH、-OH、-N(C1-4アルキル)2から選択される基であり、当該置換基を1〜5個、好ましくは1〜3個有してもよい。なお、Yが単結合のとき、Zは置換されていてもよいヘテロ環又は-CO2Hが特に好ましい。 Preferred compounds in the compound (I) of the present invention are the following compounds:
(1) X is a lower alkenylene, -R 00 -O-CO -, - R 00 -O-CO-NR 4 - or -R 00 -O-CO-NR 4 -R 00 -;
R 1 is the same or different from each other, and is —H, —R 0 , halogen, —OR 0 , —NR 4 —CO—R 0 , an optionally substituted heterocycle, or —R 00 —substituted A good heterocycle;
R 2 and R 3 are the same or different and are —H, lower alkyl, halogen, —NO 2 , —CN, or lower alkyl substituted with halogen, provided that R 2 and R 3 are not simultaneously —H; and
B is phenylene, tetrahydropyrandiyl or a group selected from the following formulas (i) to (iv)
Figure 2007186422
 (Where k: 0, 1 or 2;
q: 0, 1 or 2;
m: 1 or 2;
R 5 and R 6 are the same or different from each other, —H or lower alkyl, or R 5 and R 6 may be combined to form an oxo group, or R 5 and R 6 are combined to form a hetero As lower alkylene, optionally interrupted by atoms, B may form a bridged or spiro ring);
A compound that is
(2) A is a bicyclic heterocyclic group in which a benzene ring and a monocyclic heterocycle are condensed, or phenyl, more preferably phenyl or phenyl in which a monocyclic 5- to 6-membered heterocyclic ring is condensed. Compound.
(3) X is a lower alkenylene, -R 00 -O-CO -, - R 00 -O-CO-NR 4 - or -R 00 -O-CO-NR 4 -R 00 - those compounds. In particular, when B is a group represented by the above formula (i) or (iv), a compound in which X is lower alkenylene or -R 00 -O-CO- is more preferable, more preferably a C 3-5 alkenylene or -R 00 -O-CO-, more preferably propylene or -R 00 -O-CO-, particularly preferably (E) -CH = CH-CH 2 -or -CH 2 -O-CO- A compound. The other hand, group B is represented by the formula (ii) or (iii), or a phenylene or tetrahydropyran-diyl, X is a lower alkenylene, -R 00 -O-CO-NR 4 - or -R 00 -O A compound represented by —CO—NR 4 —R 00 — is more preferred, and a compound represented by —R 00 —O—CO—NR 4 — or —R 00 —O—CO—NR 4 —R 00 — is more preferred. is there. R 00 is preferably C 1-3 alkylene, particularly methylene, and R 4 is preferably —H or methyl.
(4) R 1 is the same or different from each other, -H, -R 0 , halogen, -OR 0 , -R 00 -OH, -R 00 -NR 4 -R 0 , an optionally substituted heterocycle, Or -R 00 -a compound which is an optionally substituted heterocycle. More preferably, -R 0 , halogen, -OR 0 , -R 00 -OH, -R 00 -NR 4 -R 0 , an optionally substituted heterocycle, or -R 00 -optionally substituted heterocycle A compound that is a ring. R 00 is preferably C 1-3 alkylene, R 4 is preferably —H or methyl, and the heterocyclic is preferably a monocyclic 5 to 6-membered heterocyclic group. Further, preferred substituents in the “optionally substituted heterocycle” and the “optionally substituted aryl” are in particular —CO 2 H, —CO 2 —C 1-4 alkyl and methyl.
(5) A compound wherein n is 1 or 2.
(6) A compound in which R 2 and R 3 are the same or different and are lower alkyl substituted with —H, halogen, —CN, —NO 2 or halogen. More preferably a compound which is —Cl, —NO 2 or a trifluoromethyl group.
(7) The compound wherein B is phenylene, piperidinediyl, piperazinediyl, tetrahydropyrandiyl, morpholinediyl, pyrrolidinediyl, homopiperazinediyl or 8-azabicyclo [3.2.1] octanediyl. More preferably, the compound is phenylene, pyrrolidinediyl, piperidinediyl or piperazinediyl.
(8) Y is a single bond, -R 00 -, - CO- R 00 -, - NR 4 -R 00 -, - OR 00 -, - CO 2 -R 00 -, - CO-NR 4 -R 00 The compound which is-, -NR 4 -CO-R 00 -or -R 00 -OR 00- . In particular, when B is a group represented by the above formula (i) or (ii), or phenylene or tetrahydropyrandiyl, Y is a single bond, -R 00- , -NR 4 -R 00- , -OR 00- , A compound that is —CO—NR 4 —R 00 — or —NR 4 —CO—R 00 — is more preferred. On the other hand, when B is a group represented by the above formula (iii) or (iv), Y is a single bond, -R 00- , -CO-R 00- , -CO 2 -R 00- , -CO-NR 4 -R 00 -or -R 00 -OR 00- is more preferred. R 00 is preferably C 1-3 alkylene, and R 4 is preferably —H or methyl.
(9) Z is -H, -R 0 , optionally substituted heterocycle, -CO 2 H, -CO-NH 2 , -OH, -SO 2 -R 0 , -NR 4 -R 0 ,- A compound which is a heterocyclic ring optionally substituted by NR 4 —CO—R 0 , —NR 4 —SO 2 —R 0 , —CO—NR 4 —R 0 , —CO—R 0 or —CO—. R 0 is preferably C 1-3 alkyl, particularly methyl, and R 4 is preferably —H or methyl. The heterocycle is preferably a monocyclic 5- to 6-membered heterocycle, more preferably tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl, imidazolyl or pyridinyl. Here, the preferred substituents of the "heterocycle which may be substituted" and "aryl which may be substituted", -C 1-4 alkyl, -C 1-4 alkylene--OH, -OH, -N (C 1-4 alkyl) 2 is a group selected from 2 and may have 1 to 5, preferably 1 to 3 such substituents. When Y is a single bond, Z is particularly preferably an optionally substituted heterocycle or —CO 2 H.

化合物（Ｉ）の塩としては製薬学的に許容される塩である。具体的には塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の無機酸、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸、アスパラギン酸、グルタミン酸等の有機酸との酸付加塩等が挙げられる。又、置換基の種類によっては、塩基との塩を形成する場合もあり、例えば、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウム等の金属を含む無機塩基、或いはメチルアミン、エチルアミン、エタノールアミン、リジン、オルニチン等の有機塩基との塩やアンモニウム塩等が挙げられる。   The salt of compound (I) is a pharmaceutically acceptable salt. Specifically, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid And acid addition salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid and glutamic acid. Further, depending on the type of substituent, it may form a salt with a base, for example, an inorganic base containing a metal such as sodium, potassium, magnesium, calcium, aluminum, or methylamine, ethylamine, ethanolamine, lysine, Examples thereof include salts with organic bases such as ornithine and ammonium salts.

化合物（Ｉ）には、置換基の種類によっては、各種の異性体、例えばシス−トランス等の幾何異性体やケト−エノール等の互変異性体が存在する場合があるが、本発明にはこれらの異性体の分離したもの、或いは混合物が包含される。更に化合物（Ｉ）は、不斉炭素原子を有する場合があり、不斉炭素原子に基づく異性体が存在しうる。化合物（Ｉ）はこれらの異性体の混合物や単離されたものを包含する。又、化合物（Ｉ）は、置換基の種類によっては、Ｎ−オキシドを形成する場合もあり、これらのＮ−オキシド体も包含される。更に化合物（Ｉ）の各種の水和物や溶媒和物及び結晶多形の物質をも包含される。
なお、化合物（Ｉ）には、生体内において代謝されて化合物（Ｉ）又はその塩に変換される化合物、いわゆるプロドラッグもすべて包含される。このプロドラッグを形成する基としては、Prog. Med. 5:2157-2161(1985)に記載されている基や廣川書店1990年刊「医薬品の開発」第７巻 分子設計163-198に記載されている基が挙げられる。 Depending on the type of substituent, compound (I) may have various isomers, for example, geometric isomers such as cis-trans and tautomers such as keto-enol. The separated thing or mixture of these isomers is included. Furthermore, compound (I) may have an asymmetric carbon atom, and an isomer based on the asymmetric carbon atom may exist. Compound (I) includes a mixture of these isomers and an isolated one. In addition, compound (I) may form an N-oxide depending on the type of substituent, and these N-oxides are also included. Furthermore, various hydrates and solvates of compound (I) and polymorphic substances are also included.
Compound (I) includes all compounds that are metabolized in vivo and converted to compound (I) or a salt thereof, so-called prodrugs. Examples of groups that form this prodrug include those described in Prog. Med. 5: 2157-2161 (1985) and those described in Yodogawa Shoten 1990 “Development of Drugs”, Volume 7, Molecular Design 163-198. Group.

（製造法）
本発明化合物及びその製薬学的に許容される塩は、その基本骨格或いは置換基の種類に基づく特徴を利用し、種々の公知の合成法を適用して製造することができる。その際、官能基の種類によっては、当該官能基を原料乃至中間体の段階で適当な保護基で保護、又は当該官能基に容易に転化可能な基に置き換えておくことが製造技術上効果的な場合がある。このような官能基としては例えばアミノ基、水酸基、カルボニル基、カルボキシル基等であり、それらの保護基としては例えばグリーン(T. W. Greene)及びウッツ(P. G. M. Wuts)著、「Protective Groups in Organic Synthesis（第3版、1999年、John Wiley & Sons）」に記載の保護基を挙げることができ、これらを反応条件に応じて適宜選択して用いればよい。このような方法では、当該保護基を導入して反応を行った後、必要に応じて保護基を除去、或いは所望の基に転化することにより、所望の化合物を得ることができる。
又、本発明化合物のプロドラッグは上記保護基と同様、原料乃至中間体の段階で特定の基を導入、或いは得られた本発明化合物を用い反応を行うことで製造できる。反応は通常のエステル化、アミド化、脱水等、当業者により公知の方法を適用することにより行うことができる。
以下本発明化合物の代表的な製造法を説明する。 (Production method)
The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using characteristics based on the basic skeleton or the type of substituent. In this case, depending on the type of functional group, it is effective in terms of production technology to protect the functional group with an appropriate protective group at the raw material or intermediate stage, or to replace it with a group that can be easily converted to the functional group. There is a case. Examples of such a functional group include an amino group, a hydroxyl group, a carbonyl group, and a carboxyl group. Examples of protective groups for these functional groups include Protective Groups in Organic Synthesis (No. 1) by TW Greene and PGM Wuts. 3rd edition, 1999, John Wiley & Sons) ”, and these may be appropriately selected and used according to the reaction conditions. In such a method, after carrying out the reaction by introducing the protective group, the desired compound can be obtained by removing the protective group or converting it to a desired group as necessary.
Similarly to the protecting group, a prodrug of the compound of the present invention can be produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound of the present invention. The reaction can be carried out by applying a method known by those skilled in the art, such as ordinary esterification, amidation, dehydration and the like.
Hereinafter, typical production methods of the compound of the present invention will be described.

製法A アルキル化（１）

Figure 2007186422
（式中、L1は脱離基、X1はR00又は低級アルケニレン、Ｂ'はＢのうち環原子として窒素原子を有するヘテロ環を示す。以下同様。）
本製法は、化合物（II）と化合物（IIIa）とを反応させ、本発明化合物（Ia）を得る方法である。ここで、L1の脱離基としては、例えばハロゲン原子、メチルスルホニルオキシ、p-トルエンスルホニルオキシ、アセトキシ基等が挙げられる。
反応は、化合物（II）と化合物（IIIa）とを等量若しくは一方を過剰量用い、ベンゼン、トルエン、キシレン等の芳香族炭化水素類、ジエチルエーテル、テトラヒドロフラン（THF）、ジオキサン等のエーテル類、塩化メチレン、1,2-ジクロロエタン、クロロホルム等のハロゲン化炭化水素類、N,N-ジメチルホルムアミド（DMF）、ジメチルアセトアミド（DMA）、N-メチルピロリドン（NMP）、酢酸エチル、アセトニトリル等反応に不活性な溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは０℃から８０℃で行うことができる。トリエチルアミン、N,N-ジイソプロピルエチルアミン若しくはN-メチルモルホリン等の有機塩基、又は炭酸カリウム、炭酸ナトリウム若しくは水酸化カリウム等の無機塩基の存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。又、化合物によっては、パラジウムなどの遷移金属或いはそのホスフィン錯体の存在下に行うのが有利な場合がある。例えば日本化学会編「実験化学講座（丸善）」（第４版、２０巻、１９９２年、２８４）等に記載の方法が適用できる。
化合物（IIIa）の代わりに、環外にアミノ基を有する原料化合物（IIIb）を用いても、同様にアルキル化反応を行うことができる。
Figure 2007186422
 （式中、X2は単結合又はR00を示す。以下同様。）
製法B アルキル化（２）
Figure 2007186422
 （式中、X3は単結合、R00又は低級アルケニレンを示す。以下同様。）
本製法は、化合物（IV）と化合物（IIIa）との還元的アルキル化反応により、本発明化合物（Ib）を得る方法である。
反応は、化合物（IV）と化合物（IIIa）とを等量若しくは一方を過剰量用い、これらの混合物を、等量若しくは過剰量のシアン化水素化ホウ素ナトリウム、トリアセトキシ水素化ホウ素ナトリウム[NaBH(OAc)3]、水素化ホウ素ナトリウム等の還元剤で処理することにより行われる。通常、メタノール、エタノール等のアルコール類、ハロゲン化炭化水素類、エーテル類、芳香族炭化水素類等の溶媒中、酢酸、塩酸等の酸、チタニウム（IV）イソプロポキシド、四塩化チタン、三フッ化ホウ素エーテル錯体等のルイス酸、或いはモレキュラーシーブス等の脱水剤の存在下、又は非存在下で、−２０℃から加熱還流下、好ましくは０℃から室温で行うことができる。中間体としてイミン体を一旦単離し、還元反応を行っても良い。又、前記還元剤での処理の代わりにメタノール、エタノール、酢酸エチル、酢酸等の溶媒中、酢酸、塩酸等の酸の存在下、又は非存在下で、還元触媒（例えば、パラジウム炭素、ラネーニッケル等）を用いて、常圧から５０気圧の水素雰囲気下で、０℃から１００℃で行うことができる。
化合物（IIIa）の代わりに、環外にアミノ基を有する誘導体（IIIb）を用いても、同様にアルキル化反応を行うことができる。
製法C オレフィン化
Figure 2007186422
 （式中、X4は単結合又はC1-3アルキレン、pは1〜3、L2は脱離基を示す。）
本製法は、化合物（V）と化合物（VI）及び（IIIa）とを反応させ、本発明化合物（Ic）を得る方法である。ここで、L2の脱離基としては、例えばハロゲン原子が挙げられる。
本反応は、化合物（V）に対し、等量若しくは過剰量の化合物（VI）及び化合物（IIIa）を用い、これらの混合物を、等量若しくは過剰量のリチウム ジイソプロピルアミド、水素化ナトリウム、アルキルリチウム、フェニルリチウム、カリウム ｔ−ブトキシド、炭酸カリウム等の塩基で処理することにより行われる。通常、ジエチルエーテル、THF、DMF、エタノール、イソプロパノール等の溶媒中、冷却下から加熱還流下、好ましくは室温から１００℃で行うことができる。ヨウ化テトラｎ−ブチルアンモニウム等の相間移動触媒存在下に反応させるのが、反応を円滑に進行させる上で有利な場合がある。
化合物（IIIa）の代わりに、環外にアミノ基を有する原料化合物（IIIb）を用いても、同様にオレフィン化反応を行うことができる。
製法D カルバマート化
Figure 2007186422
 （式中、L3は脱離基を示す。）
本製法は、化合物（VII）とイソシアナート化合物（VIIIa）を反応させることにより、或いは炭酸エステル誘導体（IX）へと変換後、化合物（IIIa）と反応させることにより、本発明化合物（1d）又は（1e）を得る方法である。ここで、L3の脱離基としては、例えばクロロ基、イミダゾリル基、フェニル基、4-ニトロフェニル基等が挙げられる。
前者の反応においては、化合物（VII）及び（VIIIa）を等量若しくは一方を過剰量用いて、これらを混合することにより行われる。反応は、ハロゲン化炭化水素類、芳香族炭化水素類、エーテル類、アセトニトリル、DMF等の反応に不活性な有機溶媒中、又は無溶媒下、冷却下から加熱還流下、好ましくは０℃から室温で行うことができる。イソシアナート化合物（VIIIa）は、対応する酸アジド化合物のCurtius転位、或いは一級アミド化合物のHoffmann転位等により製造できる。当該酸アジドは、カルボン酸の反応性誘導体とアジ化ナトリウム等のアジ化物塩との反応、又はカルボン酸とジフェニルホスホリルアジド（DPPA）との反応により製造できる。
後者の反応においては、まず、化合物（VII）をハロゲン化炭化水素類やアセトニトリル等の反応に不活性な溶媒中、有機塩基又は無機塩基存在下で、ジホスゲン、トリホスゲン、1,1'-カルボニルジイミダゾール（CDI）、クロロギ酸 4-ニトロフェニル、クロロギ酸フェニル等のカルボニル化試薬で処理し、次いで、反応系中で等量若しくは過剰量の化合物（IIIa）と反応させる。本反応は、冷却下から加熱還流下、好ましくは０℃から８０℃で行われる。クロロギ酸 4-ニトロフェニル又はクロロギ酸フェニルを使用する場合、中間体であるフェニルカルボナート体（IX）を一旦単離して反応を行っても良い。
化合物（IIIa）の代わりに、環外にアミノ基を有する原料化合物（IIIb）を用いても、同様にカルバマート化反応を行うことができる。
製法E 置換反応
Figure 2007186422
 （式中、L4、L5は脱離基を示す。）
本製法は、化合物（XI）とチオール誘導体（X）、若しくは化合物（XII）とチオール誘導体（XIII）を反応させ、本発明化合物（Ｉ）を得る方法である。ここで、L4、L5の脱離基としては、例えばハロゲン原子、トリフルオロメタンスルホニルオキシ基、ジアゾニウム基等が挙げられる。反応は、例えば日本化学会編「実験化学講座（丸善）」（第４版、２４巻、１９９２年、３３６）、Org. Lett., 3517-3520 (2002) 等に記載の方法が適用できる。 Process A Alkylation (1)
Figure 2007186422
 (In the formula, L 1 represents a leaving group, X 1 represents R 00 or lower alkenylene, and B ′ represents a heterocyclic ring having a nitrogen atom as a ring atom of B. The same shall apply hereinafter.)
This production method is a method for obtaining the compound (Ia) of the present invention by reacting the compound (II) with the compound (IIIa). Here, examples of the leaving group for L 1 include a halogen atom, methylsulfonyloxy, p-toluenesulfonyloxy, acetoxy group, and the like.
In the reaction, compound (II) and compound (IIIa) are used in an equal amount or in an excess amount, and aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran (THF) and dioxane, Not suitable for halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform, N, N-dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), ethyl acetate, acetonitrile, etc. The reaction can be carried out in an active solvent or without a solvent, under cooling to heating under reflux, preferably at 0 to 80 ° C. The reaction in the presence of an organic base such as triethylamine, N, N-diisopropylethylamine or N-methylmorpholine, or an inorganic base such as potassium carbonate, sodium carbonate or potassium hydroxide is advantageous for the smooth progress of the reaction. There are cases. Depending on the compound, it may be advantageous to carry out the reaction in the presence of a transition metal such as palladium or a phosphine complex thereof. For example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, Volume 20, 1992, 284) can be applied.
The alkylation reaction can be carried out in the same manner by using the raw material compound (IIIb) having an amino group outside the ring instead of the compound (IIIa).
Figure 2007186422
 (In the formula, X 2 represents a single bond or R 00. The same shall apply hereinafter.)
Process B Alkylation (2)
Figure 2007186422
 (In the formula, X 3 represents a single bond, R 00 or lower alkenylene. The same shall apply hereinafter.)
This production method is a method for obtaining the compound (Ib) of the present invention by reductive alkylation reaction between the compound (IV) and the compound (IIIa).
In the reaction, compound (IV) and compound (IIIa) are used in an equal amount or in an excess amount, and a mixture of these is used in an equal amount or an excess amount of sodium cyanoborohydride, sodium triacetoxyborohydride [NaBH (OAc) 3 ], by treating with a reducing agent such as sodium borohydride. Usually, in solvents such as alcohols such as methanol and ethanol, halogenated hydrocarbons, ethers and aromatic hydrocarbons, acids such as acetic acid and hydrochloric acid, titanium (IV) isopropoxide, titanium tetrachloride, trifluoride The reaction can be carried out at −20 ° C. under heating under reflux, preferably at 0 ° C. to room temperature, in the presence or absence of a Lewis acid such as boron halide ether complex or a dehydrating agent such as molecular sieves. An imine compound may be once isolated as an intermediate and subjected to a reduction reaction. Further, instead of the treatment with the reducing agent, a reduction catalyst (for example, palladium carbon, Raney nickel, etc.) in a solvent such as methanol, ethanol, ethyl acetate, acetic acid, in the presence or absence of an acid such as acetic acid, hydrochloric acid, etc. ) In a hydrogen atmosphere at atmospheric pressure to 50 atm.
The alkylation reaction can be similarly carried out using a derivative (IIIb) having an amino group outside the ring instead of the compound (IIIa).
Process C Olefination
Figure 2007186422
 (In the formula, X 4 represents a single bond or C 1-3 alkylene, p represents 1 to 3, and L 2 represents a leaving group.)
This production method is a method for obtaining the compound (Ic) of the present invention by reacting the compound (V) with the compounds (VI) and (IIIa). Here, examples of the leaving group for L 2 include a halogen atom.
In this reaction, an equal or excess amount of compound (VI) and compound (IIIa) is used with respect to compound (V), and a mixture of these is converted to an equal or excess amount of lithium diisopropylamide, sodium hydride, alkyllithium. , Phenyl lithium, potassium t-butoxide, potassium carbonate and the like. Usually, the reaction can be carried out in a solvent such as diethyl ether, THF, DMF, ethanol, and isopropanol under cooling to heating under reflux, preferably at room temperature to 100 ° C. In some cases, the reaction in the presence of a phase transfer catalyst such as tetra-n-butylammonium iodide is advantageous for smoothly proceeding the reaction.
The olefination reaction can be carried out in the same manner by using the raw material compound (IIIb) having an amino group outside the ring instead of the compound (IIIa).
Process D Carbamate
Figure 2007186422
 (In the formula, L 3 represents a leaving group.)
This production method comprises reacting compound (VII) with isocyanate compound (VIIIa), or converting to carbonate ester derivative (IX) and then reacting with compound (IIIa) to produce compound (1d) or This is a method for obtaining (1e). Here, examples of the leaving group for L 3 include a chloro group, an imidazolyl group, a phenyl group, and a 4-nitrophenyl group.
The former reaction is carried out by mixing the compounds (VII) and (VIIIa) in an equal amount or using one of them in an excess amount. The reaction is carried out in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, acetonitrile, DMF, or without solvent, from cooling to heating under reflux, preferably from 0 ° C. to room temperature. Can be done. The isocyanate compound (VIIIa) can be produced by the Curtius rearrangement of the corresponding acid azide compound or the Hoffmann rearrangement of the primary amide compound. The acid azide can be produced by reacting a reactive derivative of carboxylic acid with an azide salt such as sodium azide, or reacting carboxylic acid with diphenylphosphoryl azide (DPPA).
In the latter reaction, the compound (VII) is first converted to diphosgene, triphosgene, 1,1′-carbonyldioxide in a solvent inert to the reaction such as halogenated hydrocarbons or acetonitrile in the presence of an organic base or an inorganic base. It is treated with a carbonylating reagent such as imidazole (CDI), 4-nitrophenyl chloroformate, phenyl chloroformate, etc., and then reacted with an equal or excess amount of compound (IIIa) in the reaction system. This reaction is performed under cooling to heating under reflux, preferably at 0 ° C to 80 ° C. When 4-nitrophenyl chloroformate or phenyl chloroformate is used, the intermediate phenyl carbonate (IX) may be once isolated and reacted.
The carbamate-forming reaction can be similarly performed using the raw material compound (IIIb) having an amino group outside the ring instead of the compound (IIIa).
Process E Substitution reaction
Figure 2007186422
 (In the formula, L 4 and L 5 represent a leaving group.)
This production method is a method for obtaining the compound (I) of the present invention by reacting the compound (XI) and the thiol derivative (X) or the compound (XII) and the thiol derivative (XIII). Here, examples of the leaving group for L 4 and L 5 include a halogen atom, a trifluoromethanesulfonyloxy group, a diazonium group, and the like. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, 24, 1992, 336), Org. Lett., 3517-3520 (2002), etc. can be applied.

製法Ｆ その他の製法
種々の官能基を有する本発明化合物は、当業者に自明の方法又は公知の製造法、或いはその変法を適用することによっても製造することができる。例えば本発明化合物（Ｉ）を原料として、以下の反応を置換基R1又は-Y-Zの変換に適用することにより、本発明化合物（Ｉ）の一部を製造することができる。
Ｆ−１ アミド化
本発明化合物（Ｉ）中、アミノ基を有する化合物を種々のカルボン酸化合物、若しくはその反応性誘導体とを反応させることにより、アミド基を有する化合物を製造することができる。同様に、本発明化合物（Ｉ）中、カルボキシル基を有する化合物を種々のアミン化合物と縮合させることにより、アミド基を有する化合物を製造することができる。又、カルボン酸の代わりに、種々のスルホン酸誘導体（スルホン酸ハライドやスルホン酸無水物等の反応性誘導体が好ましい）を使用することで、種々のスルホンアミド誘導体を製造することができる。反応は、例えば日本化学会編「実験化学講座（丸善）」（第４版、２２巻、１９９２年、１３７）等に記載の方法が適用できる。
Ｆ−２：アルキル化（１）
本発明化合物（Ｉ）中、アミノ基を有する化合物を、種々のアルキル化剤（例えば、アルキルハライドやアルキルスルホン酸エステル等）と前記製法Ａと同様に反応させることで、アルキルアミノ基を有する化合物を製造することができる。
Ｆ−３：アルキル化（２）
本発明化合物（Ｉ）中、アミノ基を有する化合物を、種々のカルボニル化合物と前記製法Ｂと同様に反応させることによっても、アルキルアミノ基を有する化合物を製造することができる。
Ｆ−４：アルキル化（３）
本発明化合物（Ｉ）中、水酸基を有する化合物を、塩基存在下（例えば、炭酸カリウムや水素化ナトリウム）、種々のアルキル化剤（例えば、アルキルハライドやアルキルスルホン酸エステル等）と反応させることにより、アルコキシ基を有する化合物を製造することができる。反応は、例えば日本化学会編「実験化学講座（丸善）」（第４版、２０巻、１９９２年、１８７）等に記載の方法が適用できる。
Ｆ−５：アミノ化
本発明化合物（Ｉ）中、ハロゲン原子を有する化合物を一級又は二級アミン化合物と反応させることで、アミノ基を有する化合物を製造することができる。又、化合物（Ｉ）中、水酸基を有する化合物の場合には、この水酸基を種々の脱離基（例えば、ハロゲン原子やトリフルオロメタンスルホニルオキシ等）へと変換した後、同様の反応を行うことにより置換アミノ化合物を製造することができる。尚、脱離基を芳香環内に有する化合物を反応させる場合には、パラジウムなどの遷移金属或いはそのホスフィン錯体の存在下に行う。反応は、例えばJ. Org. Chem., 1144-1157 (2000)等に記載の方法が適用できる。 Production Method F Other Production Methods The compounds of the present invention having various functional groups can also be produced by applying methods that are obvious to those skilled in the art or known production methods, or modifications thereof. For example, a part of the compound (I) of the present invention can be produced by applying the following reaction to the conversion of the substituent R 1 or -YZ using the compound (I) of the present invention as a raw material.
F-1 Amidation In the compound (I) of the present invention, a compound having an amide group can be produced by reacting a compound having an amino group with various carboxylic acid compounds or reactive derivatives thereof. Similarly, in the compound (I) of the present invention, a compound having an amide group can be produced by condensing a compound having a carboxyl group with various amine compounds. Moreover, various sulfonamide derivatives can be produced by using various sulfonic acid derivatives (preferably reactive derivatives such as sulfonic acid halides and sulfonic acid anhydrides) instead of carboxylic acids. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, volume 22, 1992, 137) can be applied.
F-2: Alkylation (1)
In the compound (I) of the present invention, the compound having an amino group is reacted with various alkylating agents (for example, alkyl halides, alkyl sulfonates, etc.) in the same manner as in the above-mentioned production method A. Can be manufactured.
F-3: Alkylation (2)
A compound having an alkylamino group can also be produced by reacting a compound having an amino group in the compound (I) of the present invention with various carbonyl compounds in the same manner as in Production Method B.
F-4: Alkylation (3)
In the compound (I) of the present invention, a compound having a hydroxyl group is reacted with various alkylating agents (for example, alkyl halides and alkylsulfonic acid esters) in the presence of a base (for example, potassium carbonate and sodium hydride). A compound having an alkoxy group can be produced. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” edited by The Chemical Society of Japan (4th edition, Volume 20, 1992, 187) can be applied.
F-5: Amination In the compound (I) of the present invention, a compound having an amino group can be produced by reacting a compound having a halogen atom with a primary or secondary amine compound. In the case of a compound having a hydroxyl group in compound (I), the hydroxyl group is converted into various leaving groups (for example, halogen atom, trifluoromethanesulfonyloxy, etc.), and then the same reaction is performed. Substituted amino compounds can be prepared. In addition, when reacting the compound which has a leaving group in an aromatic ring, it carries out in presence of transition metals, such as palladium, or its phosphine complex. For the reaction, for example, the method described in J. Org. Chem., 1144-1157 (2000) can be applied.

製法Ｇ 原料化合物の製法
前記製法にて使用した原料化合物は、例えば下記合成経路に従って製造できる。

Figure 2007186422
（式中、Halはハロゲンを、R8は低級アルキル又はベンジル等のカルボキシル基の保護基を示す。）
上記式中、置換反応は前記製法Ｅと同様にして行うことができる。還元、酸化、ハロゲン化及びオレフィン化は、公知の反応を用いて実施することができる。反応は、例えば日本化学会編「実験化学講座（丸善）」（第４版、１９９２年）等に記載の方法が適用できる。 Manufacturing method G Manufacturing method of raw material compound The raw material compound used by the said manufacturing method can be manufactured according to the following synthetic pathway, for example.
Figure 2007186422
 (In the formula, Hal represents halogen, and R 8 represents a protecting group for a carboxyl group such as lower alkyl or benzyl.)
In the above formula, the substitution reaction can be carried out in the same manner as in the above production method E. Reduction, oxidation, halogenation and olefination can be carried out using known reactions. For the reaction, for example, the method described in “Chemical Experiment Course (Maruzen)” (4th edition, 1992) edited by the Chemical Society of Japan can be applied.

このようにして製造された化合物（Ｉ）は、遊離のまま、又は常法による造塩処理を施し、その塩として単離、精製される。単離、精製は抽出、濃縮、留去、結晶化、濾過、再結晶、各種クロマトグラフィー等の通常の化学操作を適応して行われる。
各種の異性体は異性体間の物理化学的な性質の差を利用して常法により単離できる。例えば光学異性体は、ラセミ化合物を光学活性な有機酸（酒石酸等）とのジアステレオマー塩に導いた後に分別再結晶する方法、或いはキラル充填材を用いたカラムクロマトグラフィー等の手法により、各々分離精製することができる。又、光学活性化合物は適切な光学活性化合物を原料として用いることにより製造することもできる。尚、ジアステレオマーの混合物についても、分別結晶化又はクロマトグラフィー等により分離することができる。 The compound (I) thus produced is isolated or purified as it is in the free state or subjected to a salt formation treatment by a conventional method. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.
Various isomers can be isolated by a conventional method utilizing the difference in physicochemical properties between the isomers. For example, optical isomers can be obtained by introducing a racemic compound into a diastereomeric salt with an optically active organic acid (such as tartaric acid), followed by fractional recrystallization, or by column chromatography using a chiral filler. It can be separated and purified. The optically active compound can also be produced by using an appropriate optically active compound as a raw material. A mixture of diastereomers can also be separated by fractional crystallization or chromatography.

（試験方法）
本発明化合物の効果は以下の薬理試験により確認された。
（１）細胞接着阻害作用
細胞接着阻害作用の評価は、ヒト血管内皮細胞株であるＥＣＶ３０４とヒトＴリンパ球のジャーカットＴ細胞株を用いて行った。（尚、ＥＣＶ３０４細胞はその細胞表面に、主たる接着分子としてＩＣＡＭ−１を発現しており、本発明者は、市販のＩＣＡＭ−１及びＬＦＡ−１の抗体が、各々ＥＣＶ３０４とジャーカットＴ細胞との接着をほぼ完全に抑制することを確認した。）
ＥＣＶ３０４は９６穴平底プレートに１．８ｘ１０4個／２００μｌ １０％ＦＢＳ ＲＰＭＩ１６４０／ウェルの密度で撒き、３７℃ ＣＯ2インキュベータ中で一晩培養し、細胞をウェル上で伸展させたものをアッセイに用いた。次に予め２０μＭカルセインＡＭ（和光純薬）で一時間ラベルしたジャーカットＴ細胞を１ｘ１０6個／ｍｌ １０％ＦＢＳ ＲＰＭＩ１６４０に調製した後、最終濃度が２ｍＭになるようにＭｎＣｌ2を添加した。これに最終濃度の１００倍濃度に調製した化合物溶液を１／１００量添加し、室温で１５分間インキュベートした。ＥＣＶ３０４の培養上清を取り除いた後、各ウェルに１ｘ１０5個／０．１ｍｌずつ添加し、３７℃ ＣＯ2インキュベータ中で３０分インキュベートした。インキュベート後、各ウェルの上清を除去し、ＰＢＳ（−）を加えて洗浄するという操作を三回繰り返したのち、２ｍＭ ＥＤＴＡ-４Ｎａ ０．５％Ｔｒｉｔｏｎ−Ｘ溶液を１００μｌずつ添加し、細胞を溶解させた。プレートを軽くプレートシェイカーで攪拌した後、カルセインの蛍光強度（４８５／５３０ｎｍ）をＣｙｔｏＦｌｕｏｒII（日本パーセプティブ・リミテッド）にて測定した。試験化合物がジャーカット細胞とＥＣＶ３０４細胞との接着を1μＭで阻害する強さ（％阻害率）を算出した。
後記実施例１２、１５、２０、２９、３６、４５、５１、６０、７１、９３、９６、１０３、１０９、１３２、１３３、１４５、１７５、１８０、１８１及び１８３の各化合物は５０％以上の阻害作用を示した。 (Test method)
The effect of the compound of the present invention was confirmed by the following pharmacological test.
(1) Cell adhesion inhibitory action The cell adhesion inhibitory action was evaluated using ECV304, which is a human vascular endothelial cell line, and Jurkat T cell line of human T lymphocytes. (Note that ECV304 cells express ICAM-1 as the main adhesion molecule on the cell surface, and the present inventors have found that commercially available ICAM-1 and LFA-1 antibodies are ECV304 and Jurkat T cells, respectively. It was confirmed that the adhesion of was almost completely suppressed.)
ECV304 was plated in a 96-well flat-bottom plate at a density of 1.8 × 10 4 cells / 200 μl 10% FBS RPMI 1640 / well, cultured overnight in a 37 ° C. CO 2 incubator, and the cells were spread on the well and used for the assay. It was. Next, Jurkat T cells previously labeled with 20 μM calcein AM (Wako Pure Chemical Industries) for 1 hour were prepared in 1 × 10 6 cells / ml 10% FBS RPMI1640, and MnCl 2 was added to a final concentration of 2 mM. To this was added 1/100 volume of the compound solution prepared to a concentration 100 times the final concentration, and incubated at room temperature for 15 minutes. After removing the ECV304 culture supernatant, 1 × 10 5 cells / 0.1 ml was added to each well and incubated in a 37 ° C. CO 2 incubator for 30 minutes. After incubation, the supernatant of each well was removed, and PBS (-) was added and washed three times, and then 100 mM of 2 mM EDTA-4Na 0.5% Triton-X solution was added, and the cells were washed. Dissolved. After lightly stirring the plate with a plate shaker, the fluorescence intensity of calcein (485/530 nm) was measured with CytoFluor II (Nippon Perceptive Limited). The strength (% inhibition rate) at which the test compound inhibits adhesion between Jurkat cells and ECV304 cells at 1 μM was calculated.
The compounds of Examples 12, 15, 20, 29, 36, 45, 51, 60, 71, 93, 96, 103, 109, 132, 133, 145, 175, 180, 181 and 183 are 50% or more. Inhibitory action was shown.

（２）マウス接触性過敏反応
６〜９週令の雌性Balb/cマウスの腹部を剃毛し、７％塩化ピクリル（ＴＮＣＢ）のアセトン：オリーブオイル（４：１（ｖ／ｖ））溶液を５０μｌ塗布することにより感作した。感作の５日目にケタミン・キシラジン麻酔下で０．３％ＴＮＣＢのアセトン：オリーブオイル（４：１（ｖ／ｖ））溶液２０μｌをマウス右耳の表裏に１０μｌずつ塗布した。試験薬物投与はＴＮＣＢ溶液の塗布１時間前と６時間後に経口投与（30mg／kg）により行った。右耳介の厚みは塗布前と２４時間後にシックネスゲージ（ミツトヨ）を用いて測定した。感作を行い、５日後に溶媒のみを投与した群をコントロール群、感作なしで５日後にＴＮＣＢ溶液を塗布した群をノーマル群とし、それぞれの２４時間後の厚みの増加（腫れ）から下式により抑制率を計算した。
抑制率＝（コントロール群の腫れ−試験薬物投与群の腫れ）Ｘ１００／（コントロール群の腫れ−ノーマル群の腫れ）
本発明化合物は、経口投与で優れた抑制活性を示した。 (2) Mouse contact hypersensitivity reaction The abdomen of 6-9 week old female Balb / c mice was shaved and a 7% picryl chloride (TNCB) solution in acetone: olive oil (4: 1 (v / v)) was added. Sensitization was performed by applying 50 μl. On the 5th day of sensitization, 20 μl of 0.3% TNCB in acetone: olive oil (4: 1 (v / v)) was applied to the front and back of each mouse right ear under ketamine / xylazine anesthesia. Test drug administration was performed by oral administration (30 mg / kg) 1 hour before and 6 hours after application of the TNCB solution. The thickness of the right auricle was measured using a thickness gauge (Mitutoyo) before application and 24 hours later. The group to which sensitization was performed and only the solvent was administered 5 days later was the control group, and the group to which TNCB solution was applied 5 days after the sensitization was defined as the normal group. The inhibition rate was calculated by the formula.
Inhibition rate = (swelling in control group−swelling in test drug administration group) × 100 / (swelling in control group−swelling in normal group)
The compound of the present invention showed excellent inhibitory activity after oral administration.

一般式（Ｉ）で示された化合物の１種又は２種以上を有効成分として含有する本発明の医薬組成物は、当分野において通常用いられている薬剤用担体、賦形剤等を用いて通常使用されている方法によって調製することができる。投与は錠剤、丸剤、カプセル剤、顆粒剤、散剤、液剤等による経口投与、又は静注、筋注等の注射剤、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等の外用剤、坐剤、吸入剤等による非経口投与のいずれの形態であってもよい。   The pharmaceutical composition of the present invention containing one or more of the compounds represented by the general formula (I) as an active ingredient is prepared by using a pharmaceutical carrier, excipient, etc. that are usually used in this field. It can be prepared by a commonly used method. Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or injection such as intravenous injection, intramuscular injection, ointment, plaster, cream, jelly, poultice, spray, Any form of parenteral administration such as external preparations such as lotions, eye drops, eye ointments, suppositories, inhalants and the like may be used.

本発明による経口投与のための固体組成物としては、錠剤、散剤、顆粒剤等が用いられる。このような固体組成物においては、一つ又はそれ以上の活性物質が、少なくとも一つの不活性な賦形剤、例えば乳糖、マンニトール、ブドウ糖、ヒドロキシプロピルセルロース、微結晶セルロース、デンプン、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム等と混合される。組成物は、常法に従って、不活性な添加剤、例えばステアリン酸マグネシウム等の滑沢剤やカルボキシメチルスターチナトリウム等の崩壊剤、溶解補助剤を含有していてもよい。錠剤又は丸剤は必要により糖衣又は胃溶性若しくは腸溶性コーティング剤で被膜してもよい。
経口投与のための液体組成物は、薬剤的に許容される乳剤、液剤、懸濁剤、シロップ剤、エリキシル剤等を包含し、一般的に用いられる不活性な溶剤、例えば精製水、エタノール等を用いることができる。この組成物は不活性な溶剤以外に可溶化剤、湿潤剤、懸濁化剤のような補助剤、甘味剤、矯味剤、芳香剤、防腐剤を含有していてもよい。
非経口投与のための注射剤としては、無菌の水性又は非水性の液剤、懸濁剤、乳剤を包含する。水性の溶剤としては、例えば注射用蒸留水及び生理食塩水が含まれる。非水性の溶剤としては、例えばプロピレングリコール、ポリエチレングリコール、オリーブ油のような植物油、エタノールのようなアルコール類、ポリソルベート８０（商品名）等がある。このような組成物は、更に等張化剤、防腐剤、湿潤剤、乳化剤、分散剤、安定化剤、溶解補助剤を含んでもよい。これらは例えばバクテリア保留フィルターを通す濾過、殺菌剤の配合又は照射によって無菌化される。又、これらは無菌の固体組成物を製造し、使用前に無菌水又は無菌の注射用溶媒に溶解、懸濁して使用することもできる。 As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. Mixed with magnesium aluminate acid. The composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. If necessary, tablets or pills may be coated with a sugar coating or a gastric or enteric coating agent.
Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and generally used inert solvents such as purified water, ethanol, etc. Can be used. In addition to the inert solvent, the composition may contain adjuvants such as solubilizers, wetting agents, and suspending agents, sweeteners, corrigents, fragrances, and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solvent include distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like. Such a composition may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, and solubilizing agents. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.

外用剤としては、軟膏剤、硬膏剤、クリーム剤、ゼリー剤、パップ剤、噴霧剤、ローション剤、点眼剤、眼軟膏等を包含する。一般に用いられる軟膏基剤、ローション基剤、水性又は非水性の液剤、懸濁剤、乳剤等を含有する。例えば、軟膏又はローション基剤としては、ポリエチレングリコール、プロピレングリコール、白色ワセリン、サラシミツロウ、ポリオキシエチレン硬化ヒマシ油、モノステアリン酸グリセリン、ステアリルアルコール、セチルアルコール、ラウロマクロゴール、セスキオレイン酸ソルビタン等が挙げられる。   External preparations include ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, eye ointments and the like. Contains commonly used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, emulsions, and the like. For example, ointment or lotion bases include polyethylene glycol, propylene glycol, white petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, etc. Can be mentioned.

本発明化合物の１日の投与量は、通常、経口投与の場合、体重当たり約０．００１から５０ｍｇ／ｋｇ、好ましくは０．０１〜３０ｍｇ／ｋｇ、更に好ましくは、０．０５〜１０ｍｇ／ｋｇが、静脈投与される場合、１日の投与量は、体重当たり約０．０００１から１０ｍｇ／ｋｇ、好ましくは０．００１〜１．０ｍｇ／ｋｇがそれぞれ適当であり、これを１日１回乃至複数回に分けて投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。又、外用剤として用いる場合は、本発明化合物を０．０００１〜２０％、好ましくは０．０１〜１０％を含む外用剤が好ましい。これを１日１〜数回、症状に応じて局所に投与する。   The daily dose of the compound of the present invention is usually about 0.001 to 50 mg / kg, preferably 0.01 to 30 mg / kg, more preferably 0.05 to 10 mg / kg per body weight in the case of oral administration. However, in the case of intravenous administration, the daily dose is about 0.0001 to 10 mg / kg, preferably 0.001 to 1.0 mg / kg per body weight. Dosing in multiple doses. The dosage is appropriately determined according to the individual case in consideration of symptoms, age, sex and the like. Moreover, when using as an external preparation, the external preparation containing 0.0001-20% of this invention compound, Preferably 0.01-10% is preferable. This is administered locally one to several times a day depending on the symptoms.

以下実施例を挙げ、本発明化合物の製造方法を具体的に説明する。なお、本発明化合物の原料化合物の製造方法を参考例として示す。
参考例１：WO2002/059132, EXAMPLE1記載の方法に従って製造した2-[4-(メトキシメトキシ)フェニル]-5,5-ジメチル-1,3-ジオキソランのTHF溶液に、-78℃で1.6M n-ブチルリチウム／ヘキサン溶液を加えてリチオ化した後、ジメチルジスルフィドを加え室温で反応させる事により、2-[4-(メトキシメトキシ)-3-(メチルスルファニル)フェニル]-5,5-ジメチル-1,3-ジオキソランを得た。FAB-MS:299 (M+H)+。
参考例２：参考例１の生成物を60℃にて1M塩酸で処理する事により、4-ヒドロキシ-3-(メチルスルファニル)ベンズアルデヒドを得た。FAB-MS:169 (M+H)+。
参考例３：参考例２の生成物を、ピリジン中でトリフルオロメタンスルホン酸無水物と反応させてトリフルオロメタンスルホン酸 4-ホルミル-2-(メチルスルファニル)フェニルエステルとした後、この塩化メチレン溶液を、等量のメタクロロ過安息香酸で処理する事により、トリフルオロメタンスルホン酸 4-ホルミル-2-(メチルスルフィニル)フェニルエステルを得た。FAB-MS:317 (M+H)+。
参考例４：参考例１の生成物を塩化メチレン中、2当量のメタクロロ過安息香酸で処理する事により、2-[4-(メトキシメトキシ)-3-(メチルスルホニル)フェニル]-5,5-ジメチル-1,3-ジオキソランを得た。FAB-MS:331 (M+H)+。
参考例５： 2-モルホリン-4-イルフェノールのアセトン溶液に、ジメチルチオカルバミン酸クロリドと炭酸カリウムを加え100℃で反応させることにより、O-(2-モルホリン-4-イルフェニル) ジメチルチオカルバマートを得た[FAB-MS:267 (M+H)+]。次いで、これをアルゴン雰囲気中、無溶媒下250℃で加熱した後、メタノール及び28%ナトリウムメトキシド／メタノール溶液を加え、加熱還流することにより、2-モルホリン-4-イルベンゼンチオールを得た。FAB-MS:196 (M+H)+。 Hereinafter, the production method of the compound of the present invention will be specifically described with reference to examples. In addition, the manufacturing method of the raw material compound of this invention compound is shown as a reference example.
Reference Example 1: To a THF solution of 2- [4- (methoxymethoxy) phenyl] -5,5-dimethyl-1,3-dioxolane prepared according to the method described in WO2002 / 059132, EXAMPLE1, 1.6 M n at −78 ° C. -Butyllithium / hexane solution was added for lithiation, and then dimethyldisulfide was added and reacted at room temperature to give 2- [4- (methoxymethoxy) -3- (methylsulfanyl) phenyl] -5,5-dimethyl- 1,3-Dioxolane was obtained. FAB-MS: 299 (M + H) + .
Reference Example 2: The product of Reference Example 1 was treated with 1M hydrochloric acid at 60 ° C. to obtain 4-hydroxy-3- (methylsulfanyl) benzaldehyde. FAB-MS: 169 (M + H) + .
Reference Example 3: The product of Reference Example 2 was reacted with trifluoromethanesulfonic anhydride in pyridine to give trifluoromethanesulfonic acid 4-formyl-2- (methylsulfanyl) phenyl ester. By treating with an equal amount of metachloroperbenzoic acid, trifluoromethanesulfonic acid 4-formyl-2- (methylsulfinyl) phenyl ester was obtained. FAB-MS: 317 (M + H) + .
Reference Example 4: The product of Reference Example 1 was treated with 2 equivalents of metachloroperbenzoic acid in methylene chloride to give 2- [4- (methoxymethoxy) -3- (methylsulfonyl) phenyl] -5,5 -Dimethyl-1,3-dioxolane was obtained. FAB-MS: 331 (M + H) + .
Reference Example 5: O- (2-morpholin-4-ylphenyl) dimethylthiocarbamate is obtained by adding dimethylthiocarbamic acid chloride and potassium carbonate to an acetone solution of 2-morpholin-4-ylphenol and reacting at 100 ° C. The mart was obtained [FAB-MS: 267 (M + H) + ]. Subsequently, this was heated in an argon atmosphere at 250 ° C. without solvent, and then methanol and 28% sodium methoxide / methanol solution were added and heated to reflux to obtain 2-morpholin-4-ylbenzenethiol. FAB-MS: 196 (M + H) + .

参考例６：4-(2-アミノエチル)ピペラジン-1-カルボン酸 t-ブチルエステルをピリジン中、無水酢酸と反応させた後、減圧下で濃縮し、次いでトリフルオロ酢酸で処理する事により、N-(2-ピペラジン-1-イルエチル)アセトアミド 二トリフルオロ酢酸塩を得た。FAB-MS:172 (M+H)+。
参考例７：ピペラジン-1-カルボン酸 t-ブチルエステルとN-(2-クロロエチル)フタルイミドを、DMF溶液中、炭酸カリウム及びヨウ化ナトリウムの存在下で反応させた後、生成物を塩酸塩として結晶化させることにより、2-(2-ピペラジン-1-イルエチル)-1H-イソインドール-1,3(2H)-ジオン 二塩酸塩を得た。FAB-MS:260 (M+H)+。
参考例８：2,3-ジクロロ-4-ヒドロキシベンズアルデヒドを、ピリジン中でトリフルオロメタンスルホン酸無水物と反応させて製造したトリフルオロメタンスルホン酸 2,3-ジクロロ-4-ホルミルフェニルエステルを、アセトニトリル中、N,N-ジイソプロピルエチルアミン存在下、室温で2-イソプロピルベンゼンチオールと反応させることにより、2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンズアルデヒドを得た。FAB-MS:325 (M+H)+。
参考例９：{2-[(2,3-ジクロロ-4-ホルミルフェニル)スルファニル]フェニル}酢酸のベンゼン／メタノール溶液を、2Mトリメチルシリルジアゾメタン／ヘキサン溶液で処理することにより、{2-[(2,3-ジクロロ-4-ホルミルフェニル)スルファニル]フェニル}酢酸 メチルエステルを得た。FAB-MS:355 (M+H)+。
参考例１０：2,3-ジクロロ-4-[(2-ヒドロキシフェニル)スルファニル]ベンズアルデヒドのDMF溶液を、炭酸カリウム存在下、ブロモ酢酸 t-ブチルエステルと反応させる事により、{2-[(2,3-ジクロロ-4-ホルミルフェニル)スルファニル]フェノキシ}酢酸 t-ブチルエステルを得た。FAB-MS:413 (M+H)+。 Reference Example 6: 4- (2-Aminoethyl) piperazine-1-carboxylic acid t-butyl ester was reacted with acetic anhydride in pyridine, then concentrated under reduced pressure, and then treated with trifluoroacetic acid. N- (2-piperazin-1-ylethyl) acetamide ditrifluoroacetate was obtained. FAB-MS: 172 (M + H) + .
Reference Example 7: After reacting piperazine-1-carboxylic acid t-butyl ester and N- (2-chloroethyl) phthalimide in a DMF solution in the presence of potassium carbonate and sodium iodide, the product was converted to hydrochloride. Crystallization gave 2- (2-piperazin-1-ylethyl) -1H-isoindole-1,3 (2H) -dione dihydrochloride. FAB-MS: 260 (M + H) + .
Reference Example 8: Trifluoromethanesulfonic acid 2,3-dichloro-4-formylphenyl ester prepared by reacting 2,3-dichloro-4-hydroxybenzaldehyde with trifluoromethanesulfonic anhydride in pyridine was dissolved in acetonitrile. 2,3-Dichloro-4-[(2-isopropylphenyl) sulfanyl] benzaldehyde was obtained by reacting with 2-isopropylbenzenethiol at room temperature in the presence of N, N-diisopropylethylamine. FAB-MS: 325 (M + H) + .
Reference Example 9: By treating a benzene / methanol solution of {2-[(2,3-dichloro-4-formylphenyl) sulfanyl] phenyl} acetic acid with a 2M trimethylsilyldiazomethane / hexane solution, {2-[(2 , 3-Dichloro-4-formylphenyl) sulfanyl] phenyl} acetic acid methyl ester was obtained. FAB-MS: 355 (M + H) + .
Reference Example 10: By reacting a DMF solution of 2,3-dichloro-4-[(2-hydroxyphenyl) sulfanyl] benzaldehyde with t-butyl ester of bromoacetic acid in the presence of potassium carbonate, {2-[(2 , 3-Dichloro-4-formylphenyl) sulfanyl] phenoxy} acetic acid t-butyl ester was obtained. FAB-MS: 413 (M + H) + .

参考例１１：2,3-ジクロロ-4-{[2-(ヒドロキシメチル)フェニル]スルファニル}ベンズアルデヒドをDMF中、t-ブチル(クロロ)ジメチルシラン及びイミダゾールで処理する事により、4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロベンズアルデヒドを得た。FAB-MS:426 (M-H)-。
参考例１２：4-[(3-ブロモフェニル)スルファニル]-2,3-ジクロロベンズアルデヒド、エチレングリコール及び触媒量のp-トルエンスルホン酸のベンゼン溶液を、脱水条件下で加熱還流してアセタール化した後、生成物をトルエン中、炭酸セシウム、触媒量の1,1'-ビナフタレン-2,2'-ジイルビス(ジフェニルホスフィン)及び酢酸パラジウムの存在下、ピペリジン-4-カルボン酸 エチルエステルと100℃で反応させ、1-(3-{[2,3-ジクロロ-4-(1,3-ジオキソラン-2-イル)フェニル]スルファニル}フェニル)ピペリジン-4-カルボン酸 エチルエステルとした。これをアセトン中、濃硫酸で処理してアセタールの加水分解を行うことにより、1-{3-[(2,3-ジクロロ-4-ホルミルフェニル)スルファニル]フェニル}ピペリジン-4-カルボン酸 エチルエステルを得た。FAB-MS:438 (M+H)+。
参考例１３：参考例１２と同様にして、1-{3-[(2,3-ジクロロ-4-ホルミルフェニル)スルファニル]フェニル}ピペリジン-3-カルボン酸 エチルエステルを製造した。FAB-MS:438 (M+H)+。
参考例１４：2,3-ジクロロ-4-{[2-(ヒドロキシメチル)フェニル]スルファニル}ベンズアルデヒドをDMF溶液中、臭化リチウム及び三臭化リンと反応させた後、生成物をN,N-ジイソプロピルエチルアミンの存在下、モルホリンと反応させることにより、2,3-ジクロロ-4-{[2-(モルホリン-4-イルメチル)フェニル]スルファニル}ベンズアルデヒドを得た。FAB-MS:382 (M+H)+。
参考例１５：参考例１４と同様にして、2,3-ジクロロ-4-({2-[(ジメチルアミノ)メチル]フェニル}スルファニル)ベンズアルデヒドを製造した。FAB-MS:339 (M+H)+。 Reference Example 11: By treating 2,3-dichloro-4-{[2- (hydroxymethyl) phenyl] sulfanyl} benzaldehyde with t-butyl (chloro) dimethylsilane and imidazole in DMF, 4-{[2 -({[t-Butyl (dimethyl) silyl] oxy} methyl) phenyl] sulfanyl} -2,3-dichlorobenzaldehyde was obtained. FAB-MS: 426 (MH) - .
Reference Example 12: 4-[(3-bromophenyl) sulfanyl] -2,3-dichlorobenzaldehyde, ethylene glycol and a catalytic amount of p-toluenesulfonic acid in benzene were heated to reflux under dehydrating conditions to acetalize. Afterwards, the product in toluene with cesium carbonate, catalytic amounts of 1,1'-binaphthalene-2,2'-diylbis (diphenylphosphine) and palladium acetate at 100 ° C with piperidine-4-carboxylic acid ethyl ester The reaction was performed to give 1- (3-{[2,3-dichloro-4- (1,3-dioxolan-2-yl) phenyl] sulfanyl} phenyl) piperidine-4-carboxylic acid ethyl ester. 1- {3-[(2,3-dichloro-4-formylphenyl) sulfanyl] phenyl} piperidine-4-carboxylic acid ethyl ester is obtained by treating the acetal with acetone in concentrated sulfuric acid. Got. FAB-MS: 438 (M + H) + .
Reference Example 13 In the same manner as in Reference Example 12, 1- {3-[(2,3-dichloro-4-formylphenyl) sulfanyl] phenyl} piperidine-3-carboxylic acid ethyl ester was produced. FAB-MS: 438 (M + H) + .
Reference Example 14: After reacting 2,3-dichloro-4-{[2- (hydroxymethyl) phenyl] sulfanyl} benzaldehyde with lithium bromide and phosphorus tribromide in DMF solution, the product was converted to N, N -By reacting with morpholine in the presence of diisopropylethylamine, 2,3-dichloro-4-{[2- (morpholin-4-ylmethyl) phenyl] sulfanyl} benzaldehyde was obtained. FAB-MS: 382 (M + H) + .
Reference Example 15 In the same manner as in Reference Example 14, 2,3-dichloro-4-({2-[(dimethylamino) methyl] phenyl} sulfanyl) benzaldehyde was produced. FAB-MS: 339 (M + H) + .

参考例１６：2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンズアルデヒドをピリジン溶液中、触媒量のピペリジン存在下、マロン酸と110℃で反応させることにより、(2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}アクリル酸を得た。FAB-MS:365 (M-H)-。
参考例１７：(2E)-3-(2,3,4-トリフルオロフェニル)アクリル酸 メチルエステルと2-イソプロピルベンゼンチオールを、参考例８と同様の条件下で反応させて得られた生成物を、1M水酸化ナトリウム水溶液で処理することにより、(2E)-3-{2,3-ジフルオロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}アクリル酸を製造した。FAB-MS:333 (M-H)-。
参考例１８：ホスホノ酢酸トリエチルをTHF中、水素化ナトリウムで処理した後、4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロベンズアルデヒドと反応させる事により、(2E)-3-(4-{[2-({t-ブチル(ジメチル)シリル}オキシ}メチル)フェニル}スルファニル}-2,3-ジクロロフェニル)アクリル酸 エチルエステルを得た。FAB-MS:496 (M-H)-。
参考例１９：(2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}アクリル酸を、トリエチルアミン存在下、クロロギ酸エチルと反応させた後、反応液を濾過し、濾液に水素化ホウ素ナトリウム及びメタノールを加えて還元反応を行うことにより、(2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-オールを得た。EI-MS:352 (M)+。
参考例２０：J. Org. Chem., 49: 1079, 1984記載の方法に従って4-[(2-イソプロピルフェニル)スルファニル]-3-(トリフルオロメチル)ベンズアルデヒドをリチオ化した後、ヘキサクロロエタンを加えてクロル化を行い、次いで参考例１６及び参考例１９と同様の反応を逐次行った後、生成物を分離精製して位置異性体(2E)-3-{2-クロロ-4-[(2-イソプロピルフェニル)スルファニル]-3-(トリフルオロメチル)フェニル}プロプ-2-エン-1-オール[FAB-MS:387 (M+H)+]及び(2E)-3-{2-クロロ-4-[(2-イソプロピルフェニル)スルファニル]-5-(トリフルオロメチル)フェニル}プロプ-2-エン-1-オール[FAB-MS:387 (M+H)+]を各々得た。 Reference Example 16: (2E) -3 by reacting 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzaldehyde with malonic acid at 110 ° C. in the presence of a catalytic amount of piperidine in a pyridine solution. -{2,3-Dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} acrylic acid was obtained. FAB-MS: 365 (MH) - .
Reference Example 17: Product obtained by reacting (2E) -3- (2,3,4-trifluorophenyl) acrylic acid methyl ester with 2-isopropylbenzenethiol under the same conditions as in Reference Example 8 Was treated with 1M aqueous sodium hydroxide solution to produce (2E) -3- {2,3-difluoro-4-[(2-isopropylphenyl) sulfanyl] phenyl} acrylic acid. FAB-MS: 333 (MH) - .
Reference Example 18: Treatment of triethyl phosphonoacetate with sodium hydride in THF followed by 4-{[2-({[t-butyl (dimethyl) silyl] oxy} methyl) phenyl] sulfanyl} -2,3-dichloro (2E) -3- (4-{[2-({t-Butyl (dimethyl) silyl} oxy} methyl) phenyl} sulfanyl} -2,3-dichlorophenyl) acrylic acid ethyl ester is reacted with benzaldehyde. Obtained. FAB-MS: 496 (MH) - .
Reference Example 19: (2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} acrylic acid was reacted with ethyl chloroformate in the presence of triethylamine, (2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2 by performing a reduction reaction by adding sodium borohydride and methanol to the filtrate. -I got En-1-ol. EI-MS: 352 (M) + .
Reference Example 20: After lithiation of 4-[(2-isopropylphenyl) sulfanyl] -3- (trifluoromethyl) benzaldehyde according to the method described in J. Org. Chem., 49: 1079, 1984, hexachloroethane was added. After chlorination, the same reaction as in Reference Example 16 and Reference Example 19 was successively carried out, and the product was separated and purified to obtain the regioisomer (2E) -3- {2-chloro-4-[(2 -Isopropylphenyl) sulfanyl] -3- (trifluoromethyl) phenyl} prop-2-en-1-ol [FAB-MS: 387 (M + H) + ] and (2E) -3- {2-chloro- 4-[(2-Isopropylphenyl) sulfanyl] -5- (trifluoromethyl) phenyl} prop-2-en-1-ol [FAB-MS: 387 (M + H) + ] was obtained.

参考例２１：参考例１８の生成物をTHF溶液中、1.0M水素化ジイソブチルアルミニウム／THF溶液で処理して還元反応を行う事により、(2E)-3-(4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロフェニル)プロプ-2-エン-1-オールを得た。FAB-MS:455 (M+H)+。
参考例２２：参考例１９の生成物を塩化メチレン中、酸化マンガンで処理する事により、(2E)-3-{2,3-ジクロロフェニル-4-[(2-イソプロピルフェニル)スルファニル]フェニル}アクリルアルデヒドを得た。FAB-MS:351 (M+H)+。
参考例２３：参考例８の生成物をメタノール中、水素化ホウ素ナトリウムで処理する事により、{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}メタノールを得た。EI-MS:326 (M)+。
参考例２４：(2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}アクリル酸をメタノール溶液中、触媒量の5%ルテニウム炭素及び活性炭の存在下、接触水素還元を行う事により、3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロピオン酸を得た。EI-MS:368 (M)+。
参考例２５：参考例２４の生成物とピペリジン-4-カルボン酸 エチルエステルを、DMF中、1-ヒドロキシベンゾトリアゾール（HOBt）及びN-[3-(ジメチルアミノ)プロピル]-N'-エチルカルボジイミド 塩酸塩（WSC・HCl）存在下縮合し、1-(3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロパノイル)ピペリジン-4-カルボン酸 エチルエステルを得た。FAB-MS:508 (M+H)+。 Reference Example 21: The product of Reference Example 18 was treated with a 1.0 M diisobutylaluminum hydride / THF solution in a THF solution to carry out a reduction reaction, whereby (2E) -3- (4-{[2-({ [t-Butyl (dimethyl) silyl] oxy} methyl) phenyl] sulfanyl} -2,3-dichlorophenyl) prop-2-en-1-ol was obtained. FAB-MS: 455 (M + H) + .
Reference Example 22: (2E) -3- {2,3-dichlorophenyl-4-[(2-isopropylphenyl) sulfanyl] phenyl} acrylic by treating the product of Reference Example 19 with manganese oxide in methylene chloride. The aldehyde was obtained. FAB-MS: 351 (M + H) + .
Reference Example 23: The product of Reference Example 8 was treated with sodium borohydride in methanol to obtain {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} methanol. EI-MS: 326 (M) + .
Reference Example 24: (2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} acrylic acid in methanol solution in the presence of catalytic amounts of 5% ruthenium carbon and activated carbon, By performing catalytic hydrogen reduction, 3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} propionic acid was obtained. EI-MS: 368 (M) + .
Reference Example 25: The product of Reference Example 24 and piperidine-4-carboxylic acid ethyl ester were mixed with 1-hydroxybenzotriazole (HOBt) and N- [3- (dimethylamino) propyl] -N′-ethylcarbodiimide in DMF. Condensation in the presence of hydrochloride (WSC / HCl) gave 1- (3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} propanoyl) piperidine-4-carboxylic acid ethyl ester . FAB-MS: 508 (M + H) + .

参考例２６：参考例２３の生成物をエチルエーテル中、三臭化リンを用いてブロム化を行う事により、1-(ブロモメチル)-2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンゼンを得た。FAB-MS:389 (M+H)+。
参考例２７：参考例１９の生成物を原料として、J. Org. Chem., 36: 3044, 1971記載の方法に従って、2,3-ジクロロ-1-[(1E)-3-クロロプロプ-1-エン-1-イル]-4-[(2-イソプロピルフェニル)スルファニル]ベンゼンを製造した。EI-MS:370 (M)+。
参考例２８：(2E)-3-(4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロフェニル)アクリルアルデヒドと1-アセチルピペラジンの塩化メチレン溶液を、NaBH(OAc)3で処理する事により1-アセチル-4-[(2E)-3-(4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロフェニル)プロプ-2-エン-1-イル]ピペラジンを得た。FAB-MS:565 (M+H)+。
参考例２９：1-アセチルピペラジンの2-プロパノール溶液に、2,3-ジクロロ-4-[(3-メトキシフェニル)スルファニル]ベンズアルデヒド、臭化(2-クロロエチル)トリフェニルホスホニウム、ヨウ化テトラ n-ブチルアンモニウム、炭酸カリウムを加え、加熱還流を行う事により、1-アセチル4-(3-{2,3-ジクロロ-4-[(3-メトキシフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジンを、E体及びZ体の混合物として得た。FAB-MS:451 (M+H)+。
参考例３０：参考例２８の生成物をTHF溶液中、フッ化テトラ n-ブチルアンモニウムで処理する事により、[2-({4-[(1E)-3-(4-アセチルピペラジン-1-イル)プロプ-1-エン-1-イル]-2,3-ジクロロフェニル}スルファニル)フェニル]メタノールを得た。FAB-MS:451 (M+H)+。 Reference Example 26: The product of Reference Example 23 was brominated with ethyl tribromide using phosphorus tribromide to give 1- (bromomethyl) -2,3-dichloro-4-[(2-isopropylphenyl). Sulfanyl] benzene was obtained. FAB-MS: 389 (M + H) + .
Reference Example 27: Using the product of Reference Example 19 as a starting material, according to the method described in J. Org. Chem., 36: 3044, 1971, 2,3-dichloro-1-[(1E) -3-chloroprop-1- En-1-yl] -4-[(2-isopropylphenyl) sulfanyl] benzene was prepared. EI-MS: 370 (M) + .
Reference Example 28: (2E) -3- (4-{[2-({[t-butyl (dimethyl) silyl] oxy} methyl) phenyl] sulfanyl} -2,3-dichlorophenyl) acrylaldehyde and 1-acetylpiperazine of methylene chloride solution, NaBH (OAc) by treatment with 3 1-acetyl -4 - [(2E) -3- ( 4 - {[2 - ({[t- butyl (dimethyl) silyl] oxy} methyl ) Phenyl] sulfanyl} -2,3-dichlorophenyl) prop-2-en-1-yl] piperazine. FAB-MS: 565 (M + H) + .
Reference Example 29: To a 2-propanol solution of 1-acetylpiperazine, 2,3-dichloro-4-[(3-methoxyphenyl) sulfanyl] benzaldehyde, (2-chloroethyl) triphenylphosphonium bromide, tetra n-iodide 1-acetyl 4- (3- {2,3-dichloro-4-[(3-methoxyphenyl) sulfanyl] phenyl} prop-2-ene-1 is obtained by adding butylammonium and potassium carbonate and heating to reflux. -Yl) Piperazine was obtained as a mixture of E-form and Z-form. FAB-MS: 451 (M + H) + .
Reference Example 30: The product of Reference Example 28 was treated with tetra n-butylammonium fluoride in a THF solution to give [2-({4-[(1E) -3- (4-acetylpiperazine-1- Yl) prop-1-en-1-yl] -2,3-dichlorophenyl} sulfanyl) phenyl] methanol. FAB-MS: 451 (M + H) + .

参考例３１：参考例３０と同様にして、1-[(2E)-3-(2,3-ジクロロ-4-{[3-(ヒドロキシメチル)フェニル]スルファニル}フェニル)プロプ-2-エン-1-イル]ピペリジン-4-カルボン酸 エチルエステルを製造した。FAB-MS:480 (M+H)+。
参考例３２：参考例３０の生成物を用い、参考例１４と同様にして、1-[2-({4-[(1E)-3-(4-アセチルピペラジン-1-イル)プロプ-1-エン-1-イル]-2,3-ジクロロフェニル}スルファニル)ベンジル]ピペリジン-3-カルボン酸 エチルエステルを製造した。FAB-MS:590 (M+H)+。
参考例３３：4-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン-1-カルボン酸 t-ブチルエステルを、4M塩化水素／酢酸エチル溶液で処理する事により、1-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン 二塩酸塩を得た。FAB-MS:421 (M+H)+。
参考例３４：1-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン 二塩酸塩と(4S)-2,2-ジメチル-1,3-ジオキソラン-4-カルボン酸を原料として、参考例２５と同様にして、1-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)-4-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]カルボニル}ピペラジンを製造した。FAB-MS:549 (M+H)+。
参考例３５：1-((2E)-3-{2,3-ジクロロ-4-[(3-メトキシフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペリジン-4-カルボン酸 エチルエステルを、塩化メチレン中、1M三臭化ホウ素／塩化メチレン溶液で処理して1-((2E)-3-{2,3-ジクロロ-4-[(3-ヒドロキシフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペリジン-4-カルボン酸 エチルエステルを得た。FAB-MS:466 (M+H)+。 Reference Example 31: In the same manner as in Reference Example 30, 1-[(2E) -3- (2,3-dichloro-4-{[3- (hydroxymethyl) phenyl] sulfanyl} phenyl) prop-2-ene- 1-yl] piperidine-4-carboxylic acid ethyl ester was prepared. FAB-MS: 480 (M + H) + .
Reference Example 32: 1- [2-({4-[(1E) -3- (4-acetylpiperazin-1-yl) prop-1] was prepared in the same manner as in Reference Example 14 using the product of Reference Example 30. -En-1-yl] -2,3-dichlorophenyl} sulfanyl) benzyl] piperidine-3-carboxylic acid ethyl ester was prepared. FAB-MS: 590 (M + H) + .
Reference Example 33: 4-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperazine-1-carboxylic acid t 1-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2 by treating 4-butyl ester with 4M hydrogen chloride / ethyl acetate solution -En-1-yl) piperazine dihydrochloride was obtained. FAB-MS: 421 (M + H) + .
Reference Example 34: 1-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperazine dihydrochloride and (4S ) -2,2-dimethyl-1,3-dioxolane-4-carboxylic acid as a starting material in the same manner as in Reference Example 25, 1-((2E) -3- {2,3-dichloro-4-[( 2-Isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) -4-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] carbonyl} piperazine was prepared . FAB-MS: 549 (M + H) + .
Reference Example 35: Ethyl 1-((2E) -3- {2,3-dichloro-4-[(3-methoxyphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperidine-4-carboxylate The ester is treated with 1M boron tribromide / methylene chloride solution in methylene chloride to give 1-((2E) -3- {2,3-dichloro-4-[(3-hydroxyphenyl) sulfanyl] phenyl} prop -2-en-1-yl) piperidine-4-carboxylic acid ethyl ester was obtained. FAB-MS: 466 (M + H) + .

参考例３６：参考例３５の生成物を、DMF中、炭酸カリウムの存在下1,3-ジオキソラン-2-オンと反応させる事により、1-[(2E)-3-(2,3-ジクロロ-4-{[3-(2-ヒドロキシエトキシ)フェニル]スルファニル}フェニル)プロプ-2-エン-1-イル]ピペリジン-4-カルボン酸 エチルエステルを得た。FAB-MS:510 (M+H)+。
参考例３７：参考例３５の生成物を、参考例３６と同様の条件下でブロモ酢酸エチルと反応させる事により、1-[(2E)-3-(2,3-ジクロロ-4-{[3-(2-エトキシ-2-オキソエトキシ)フェニル]スルファニル}フェニル)プロプ-2-エン-1-イル]ピペリジン-4-カルボン酸 エチルエステルを得た。FAB-MS:552 (M+H)+。
参考例３８：3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジル}イミダゾリジン-2,4-ジオンをDMF中、水素化ナトリウム及びブロモ酢酸エチルと反応させて(3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジル}-2,4-ジオキソイミダゾリジン-1-イル)酢酸 エチルエステルを得た。FAB-MS:495 (M+H)+。
参考例３９：参考例３８と同様にして、[3-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)-2,4-ジオキソイミダゾリジン-1-イル]酢酸 エチルエステルを製造した。FAB-MS:521 (M+H)+。
参考例４０：参考例２３の生成物を、塩化メチレン中、ピリジン存在下、クロロギ酸 4-ニトロフェニルエステルと反応させた後、得られた生成物を塩化メチレン中で、ピペリジン-4-カルボン酸 エチルエステルと反応させる事により、1-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジル} 4-エチル ピペリジン-1,4-ジカルボキシラートを得た。FAB-MS:510 (M+H)+。 Reference Example 36: The product of Reference Example 35 is reacted with 1,3-dioxolan-2-one in DMF in the presence of potassium carbonate to give 1-[(2E) -3- (2,3-dichloro -4-{[3- (2-hydroxyethoxy) phenyl] sulfanyl} phenyl) prop-2-en-1-yl] piperidine-4-carboxylic acid ethyl ester was obtained. FAB-MS: 510 (M + H) + .
Reference Example 37: The product of Reference Example 35 was reacted with ethyl bromoacetate under the same conditions as Reference Example 36 to give 1-[(2E) -3- (2,3-dichloro-4-{[ 3- (2-Ethoxy-2-oxoethoxy) phenyl] sulfanyl} phenyl) prop-2-en-1-yl] piperidine-4-carboxylic acid ethyl ester was obtained. FAB-MS: 552 (M + H) +.
Reference Example 38: 3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl} imidazolidine-2,4-dione was reacted with sodium hydride and ethyl bromoacetate in DMF ( 3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl} -2,4-dioxoimidazolidin-1-yl) acetic acid ethyl ester was obtained. FAB-MS: 495 (M + H) + .
Reference Example 39: In the same manner as in Reference Example 38, [3-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-ene-1- Yl) -2,4-dioxoimidazolidin-1-yl] acetic acid ethyl ester was prepared. FAB-MS: 521 (M + H) + .
Reference Example 40: After reacting the product of Reference Example 23 with 4-nitrophenyl ester chloroformate in the presence of pyridine in methylene chloride, the resulting product was treated with piperidine-4-carboxylic acid in methylene chloride. Reaction with ethyl ester gave 1- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl} 4-ethylpiperidine-1,4-dicarboxylate. FAB-MS: 510 (M + H) + .

参考例４１：4-オキソピペリジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステルとグリシン t-ブチルエステル 塩酸塩を原料として、参考例２８と同様にして4-[(2-t-ブトキシ-2-オキソエチル)アミノ]ピペリジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステルを製造した。FAB-MS:567 (M+H)+。
参考例４２： 4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロベンジル 4-[2-(1,3-ジオキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)エチル]ピペラジン-1-カルボキシラートを、ヒドラジン一水和物で処理してアミノ体とした後、これをピリジン中、無水酢酸で処理して4-[2-(アセチルアミノ)エチル]ピペラジン-1-カルボン酸 4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロベンジルエステルを得た。FAB-MS:626 (M+H)+。
参考例４３：4-(2-ヒドロキシエチル)ピペラジン-1-カルボン酸 2,3-ジクロロ-4-{[2-(ヒドロキシメチル)フェニル]スルファニル}ベンジルエステルを原料として、参考例２２と同様にして4-(2-ヒドロキシエチル)ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-ホルミルフェニル)スルファニル]ベンジルエステルを製造した。FAB-MS:469 (M+H)+。
参考例４４：参考例８の生成物と1-(1-トリチル-1H-イミダゾール-4-イル)エタノンを、2M水酸化ナトリウム水溶液とエタノールの混合液中で縮合し、(2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}-1-(1-トリチル-1H-イミダゾール-4-イル)プロプ-2-エン-1-オンを得た。FAB-MS:659 (M+H)+。
参考例４５：参考例８の生成物と1-(1H-ピロール-3-イル)エタノンをナトリウム メトキシド存在下縮合して得られたアルドール体を、p-トルエンスルホン酸存在下脱水することにより、(2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}-1-(1H-ピロール-3-イル)プロプ-2-エン-1-オンを得た。FAB-MS:416 (M+H)+。 Reference Example 41: 4-oxopiperidine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester and glycine t-butyl ester 4-[(2-t-butoxy-2-oxoethyl) amino] piperidine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester was prepared. FAB-MS: 567 (M + H) + .
Reference Example 42: 4-{[2-({[t-butyl (dimethyl) silyl] oxy} methyl) phenyl] sulfanyl} -2,3-dichlorobenzyl 4- [2- (1,3-dioxo-1, 3-Dihydro-2H-isoindol-2-yl) ethyl] piperazine-1-carboxylate was treated with hydrazine monohydrate to give an amino compound, which was treated with acetic anhydride in pyridine. -[2- (acetylamino) ethyl] piperazine-1-carboxylic acid 4-{[2-({[t-butyl (dimethyl) silyl] oxy} methyl) phenyl] sulfanyl} -2,3-dichlorobenzyl ester Obtained. FAB-MS: 626 (M + H) + .
Reference Example 43: 4- (2-hydroxyethyl) piperazine-1-carboxylic acid 2,3-dichloro-4-{[2- (hydroxymethyl) phenyl] sulfanyl} benzyl ester was used as a starting material in the same manner as Reference Example 22. 4- (2-hydroxyethyl) piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-formylphenyl) sulfanyl] benzyl ester was prepared. FAB-MS: 469 (M + H) + .
Reference Example 44: The product of Reference Example 8 and 1- (1-trityl-1H-imidazol-4-yl) ethanone were condensed in a mixture of 2M aqueous sodium hydroxide and ethanol, and (2E) -3- {2,3-Dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} -1- (1-trityl-1H-imidazol-4-yl) prop-2-en-1-one was obtained. FAB-MS: 659 (M + H) + .
Reference Example 45: The aldol obtained by condensing the product of Reference Example 8 and 1- (1H-pyrrol-3-yl) ethanone in the presence of sodium methoxide was dehydrated in the presence of p-toluenesulfonic acid. (2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} -1- (1H-pyrrol-3-yl) prop-2-en-1-one was obtained . FAB-MS: 416 (M + H) + .

参考例４６：参考例４５の生成物をWilkinson触媒存在下、水素雰囲気下4気圧で還元する事により、3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}-1-(1H-ピロール-3-イル)プロパン-1-オンを得た。FAB-MS:418 (M+H)+。
参考例４７：参考例４６の生成物を、カリウム t-ブトキシド存在下、ブロモ酢酸エチルでアルキル化し、[3-(3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロパノイル)-1H-ピロール-1-イル]酢酸 エチルエステルを得た。FAB-MS:504 (M+H)+。 Reference Example 46: The product of Reference Example 45 was reduced at 4 atm under hydrogen atmosphere in the presence of Wilkinson catalyst to give 3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl}- 1- (1H-pyrrol-3-yl) propan-1-one was obtained. FAB-MS: 418 (M + H) + .
Reference Example 47: The product of Reference Example 46 was alkylated with ethyl bromoacetate in the presence of potassium t-butoxide to give [3- (3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] Phenyl} propanoyl) -1H-pyrrol-1-yl] acetic acid ethyl ester was obtained. FAB-MS: 504 (M + H) + .

参考例８と同様にして４８〜７８を、参考例１１と同様にして７９〜８０を、参考例１６と同様にして８１〜９８を、参考例１８と同様にして９９〜１００を、参考例１９と同様にして１０１〜１０５及び１０８〜１２０を、参考例２１と同様にして１２１〜１２２を、参考例２２と同様にして１０６〜１０７及び１２３〜１３７を、参考例２３と同様にして１３８〜１５０を、参考例２８と同様にして１５１〜１５７及び１６１〜１７６を、参考例４０と同様にして１５８〜１６０及び１７７〜１８５を製造した。これらの構造式及び物理化学的性状を、後記表１〜表１１に示す。   48 to 78 as in Reference Example 8, 79 to 80 as in Reference Example 11, 81 to 98 as in Reference Example 16, 99 to 100 as in Reference Example 18, Reference Example In the same manner as in No. 19, 101 to 105 and 108 to 120, 121 to 122 as in Reference Example 21, 106 to 107 and 123 to 137 as in Reference Example 22, and 138 as in Reference Example 23, respectively. In the same manner as in Reference Example 28, 151 to 157 and 161 to 176 were produced, and in the same manner as Reference Example 40, 158 to 160 and 177 to 185 were produced. These structural formulas and physicochemical properties are shown in Tables 1 to 11 below.

実施例１：(2E)-3-{2,3-ジクロロフェニル-4-[(2-イソプロピルフェニル)スルファニル]フェニル}アクリルアルデヒド200 mg、3-ピペラジン-1-イルプロパン-1,2-ジオール183 mg、1,2-ジクロロエタン3 ml、NaBH(OAc)3 254 mgの混合物を室温で30分間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えてクロロホルムで抽出し、有機層を水と飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(メタノール／クロロホルム＝1／10)で精製し、得られた油状物を酢酸エチルに溶解し、4Ｍ塩化水素／酢酸エチル溶液を加えた後、溶媒を留去した。残渣をメタノールと水の混合液から再結晶して、3-[4-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン-1-イル]プロパン-1,2-ジオール 二塩酸塩113 mgを無色結晶として得た。
実施例２：2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンズアルデヒド494 mgの2-プロパノール25 ml溶液に1-アセチルピペラジン195 mg、臭化（2-クロロエチル）トリフェニルホスホニウム617 mg、ヨウ化テトラ n-ブチルアンモニウム112 mg及び炭酸カリウム1.05 gを室温で加え、20時間加熱還流した。反応終了後、溶媒を留去し、残渣に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を留去した（以後、常法による処理と略す）。残渣をシリカゲルカラムクロマトグラフィー(メタノール／クロロホルム＝2／98)で精製した。得られた油状物を酢酸エチルに溶解し、4Ｍ塩化水素／酢酸エチル溶液を加えた後、溶媒を留去した。残渣をエタノールから再結晶して、1-アセチル-4-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロパ-2-エン-1-イル)ピペラジン 塩酸塩84 mgを無色結晶として得た。
実施例３：原料として2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンズアルデヒド1171 mgと2-ピペラジン-1-イルエタノール622 mgを用い、実施例２と同様に反応を行った後、得られた粗生成物をシリカゲルカラムクロマトグラフィー(メタノール／クロロホルム＝2／98〜10／90)で精製し、高極性生成物623mgと低極性生成物132mgを得た。このうち、高極性生成物310mgを用いて、実施例２と同様に4Ｍ塩化水素／酢酸エチル溶液で処理した後に、メタノールから再結晶して、2-[4-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロパ-2-エン-1-イル)ピペラジン-1-イル]エタノール 二塩酸塩194mgを無色結晶として得た。 Example 1: (2E) -3- {2,3-dichlorophenyl-4-[(2-isopropylphenyl) sulfanyl] phenyl} acrylaldehyde 200 mg, 3-piperazin-1-ylpropane-1,2-diol 183 A mixture of mg, 1,2-dichloroethane (3 ml) and NaBH (OAc) 3 (254 mg) was stirred at room temperature for 30 minutes. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (methanol / chloroform = 1/10). The obtained oil was dissolved in ethyl acetate, and a 4M hydrogen chloride / ethyl acetate solution was added. The solvent was distilled off. The residue was recrystallized from a mixture of methanol and water to give 3- [4-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2- 113 mg of en-1-yl) piperazin-1-yl] propane-1,2-diol dihydrochloride was obtained as colorless crystals.
Example 2: 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzaldehyde 494 mg in 2-propanol 25 ml solution in 1-acetylpiperazine 195 mg, brominated (2-chloroethyl) triphenylphosphonium 617 mg, tetra n-butylammonium iodide 112 mg and potassium carbonate 1.05 g were added at room temperature, and the mixture was heated to reflux for 20 hours. After completion of the reaction, the solvent was distilled off, ethyl acetate was added to the residue, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off (hereinafter referred to as usual treatment). (Omitted). The residue was purified by silica gel column chromatography (methanol / chloroform = 2/98). The obtained oil was dissolved in ethyl acetate, 4M hydrogen chloride / ethyl acetate solution was added, and the solvent was evaporated. The residue was recrystallized from ethanol to give 1-acetyl-4-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-ene-1- Yl) piperazine hydrochloride 84 mg was obtained as colorless crystals.
Example 3: Reaction was carried out in the same manner as in Example 2 using 1171 mg of 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzaldehyde and 622 mg of 2-piperazin-1-ylethanol as raw materials. Thereafter, the obtained crude product was purified by silica gel column chromatography (methanol / chloroform = 2/98 to 10/90) to obtain 623 mg of a high polarity product and 132 mg of a low polarity product. Of these, 310 mg of a highly polar product was treated with a 4M hydrogen chloride / ethyl acetate solution in the same manner as in Example 2, and then recrystallized from methanol to give 2- [4-((2E) -3- { 194 mg of 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperazin-1-yl] ethanol dihydrochloride was obtained as colorless crystals.

実施例４：実施例３において、シリカゲルカラムクロマトグラフィーによる分離精製後に得られた低極性生成物132mgを用い、実施例３と同様にして2-[4-((2Z)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロパ-2-エン-1-イル)ピペラジン-1-イル]エタノール 二塩酸塩104mgを無色結晶として得た。
実施例５：2,3-ジクロロ-1-[(1E)-3-クロロプロプ-1-エン-1-イル]-4-[(2-イソプロピルフェニル)スルファニル]ベンゼン3.77gのアセトン80ml溶液に、ピペリジン-4-カルボン酸 エチルエステル1.62mlと炭酸カリウム1.41gを加え、室温下一晩攪拌し、更にピペリジン-4-カルボン酸 エチルエステル0.54mlと炭酸カリウム0.47gを加えて一日攪拌した。常法による処理を行った後、シリカゲルカラムクロマトグラフフィー（酢酸エチル／ヘキサン＝1／1）により精製して、1-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロパ-2-エン-1-イル)ピペリジン-4-カルボン酸 エチルエステル3.72gを淡黄色固体として得た。
実施例６：ヒダントイン31 mgをDMF1.5 mlに溶解し、炭酸カリウム31 mgを加えて30分間撹拌した後、1-(ブロモメチル)-2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンゼン111 mgのDMF1.5ml溶液を加え、室温にて14時間撹拌した。常法による処理を行った後、シリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）で精製して、3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジル}イミダゾリジン-2,4-ジオン102 mgを得た。 Example 4: In Example 3, 132 mg of a low-polarity product obtained after separation and purification by silica gel column chromatography was used in the same manner as in Example 3, and 2- [4-((2Z) -3- {2, 104 mg of 3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperazin-1-yl] ethanol dihydrochloride was obtained as colorless crystals.
Example 5: To a solution of 3.77 g of 2,3-dichloro-1-[(1E) -3-chloroprop-1-en-1-yl] -4-[(2-isopropylphenyl) sulfanyl] benzene in 80 ml of acetone, Piperidine-4-carboxylic acid ethyl ester 1.62 ml and potassium carbonate 1.41 g were added and stirred overnight at room temperature. Piperidine-4-carboxylic acid ethyl ester 0.54 ml and potassium carbonate 0.47 g were further added and stirred for one day. After the usual treatment, purification by silica gel column chromatography (ethyl acetate / hexane = 1/1) gave 1-((2E) -3- {2,3-dichloro-4-[(2 There was obtained 3.72 g of -isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperidine-4-carboxylic acid ethyl ester as a pale yellow solid.
Example 6: 31 mg of hydantoin was dissolved in 1.5 ml of DMF, 31 mg of potassium carbonate was added and stirred for 30 minutes, and then 1- (bromomethyl) -2,3-dichloro-4-[(2-isopropylphenyl) Sulfanyl] benzene (111 mg) in DMF (1.5 ml) was added, and the mixture was stirred at room temperature for 14 hours. After treatment by a conventional method, purification by silica gel column chromatography (hexane / ethyl acetate = 1/1) gave 3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl} 102 mg of imidazolidine-2,4-dione was obtained.

実施例７：{2,3-ジクロロ-4-[(3,4-ジメトキシフェニル)スルファニル]フェニル}メタノール0.61 g、ピリジン0.13 ml、塩化メチレン5.0 mlの混合物に、クロロギ酸 4-ニトロフェニルエステル363 mgを加え、14時間攪拌後、反応液を濃縮した。得られた残渣を酢酸エチルで洗浄し、2,3-ジクロロ-4-[(3,4-ジメトキシフェニル)スルファニル]ベンジル 4-ニトロフェニル カルボナート886 mgを得た。本化合物200 mgのDMF1.0 ml溶液にN-(2-ピペラジン-1-イルエチル)アセトアミド 二トリフルオロ酢酸塩155 mg及びトリエチルアミン0.14 mlを加え、室温で7時間攪拌した。反応液をクロロホルムで希釈した後、MP-carbonate（アルゴノートテクノロジー社）1.00gを加えて30分間攪拌してから濾過し、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム＝1／20）で精製し、得られた固体を酢酸エチルとメタノールの混合液に溶解し、4Ｍ塩化水素／酢酸エチル溶液を加えた。溶媒を留去して得られた残渣をアセトニトリルとメタノールの混合液から再結晶して、4-[2-(アセチルアミノ)エチル]ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(3,4-ジメトキシフェニル)スルファニル]ベンジルエステル 塩酸塩60 mgを無色結晶として得た。
実施例８：1-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジル} 4-エチル ピペリジン-1,4-ジカルボキシラート176 mgのエタノール1.5 mL溶液に1M水酸化ナトリウム水溶液414 μlを加え、室温にて6時間撹拌した。反応液に1M塩酸を加えた後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝1／1）で精製して、1-[({2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジル}オキシ)カルボニル]ピペリジン-4-カルボン酸130 mgを無色非晶性固体として得た。
実施例９：1-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペリジン-3-カルボン酸 エチルエステル277mg、アセトン5.6ml、2M塩酸11.2mlの混合物を50℃の油浴中で一日攪拌した後、更に2M塩酸5.6mlを加えて一日攪拌した。放冷後、析出した固体を濾取し、少量の氷水で洗浄後乾燥して、1-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペリジン-3-カルボン酸 塩酸塩258mgを淡褐色固体として得た。 Example 7: To a mixture of {1,3-dichloro-4-[(3,4-dimethoxyphenyl) sulfanyl] phenyl} methanol 0.61 g, pyridine 0.13 ml, methylene chloride 5.0 ml, chloroformate 4-nitrophenyl ester 363 mg was added, and after stirring for 14 hours, the reaction solution was concentrated. The obtained residue was washed with ethyl acetate to obtain 886 mg of 2,3-dichloro-4-[(3,4-dimethoxyphenyl) sulfanyl] benzyl 4-nitrophenyl carbonate. To a solution of 200 mg of this compound in 1.0 ml of DMF, 155 mg of N- (2-piperazin-1-ylethyl) acetamide ditrifluoroacetate and 0.14 ml of triethylamine were added and stirred at room temperature for 7 hours. After the reaction solution was diluted with chloroform, 1.00 g of MP-carbonate (Argonaute Technology) was added and stirred for 30 minutes, followed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / chloroform = 1/20), and the obtained solid was dissolved in a mixed solution of ethyl acetate and methanol, and 4M hydrogen chloride / ethyl acetate solution was added. The residue obtained by distilling off the solvent was recrystallized from a mixture of acetonitrile and methanol, and 4- [2- (acetylamino) ethyl] piperazine-1-carboxylic acid 2,3-dichloro-4-[(( 3,4-Dimethoxyphenyl) sulfanyl] benzyl ester hydrochloride 60 mg was obtained as colorless crystals.
Example 8: 1- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl} 4-ethyl piperidine-1,4-dicarboxylate 176 mg in ethanol 1.5 mL solution with 1M sodium hydroxide 414 μl of an aqueous solution was added and stirred at room temperature for 6 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 1-[({2,3-dichloro 130 mg of -4-[(2-isopropylphenyl) sulfanyl] benzyl} oxy) carbonyl] piperidine-4-carboxylic acid was obtained as a colorless amorphous solid.
Example 9: Ethyl 1-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperidine-3-carboxylate A mixture of 277 mg of ester, 5.6 ml of acetone and 11.2 ml of 2M hydrochloric acid was stirred in an oil bath at 50 ° C. for one day, and further 5.6 ml of 2M hydrochloric acid was added and stirred for one day. After allowing to cool, the precipitated solid was collected by filtration, washed with a small amount of ice water, dried, and 1-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl } Prop-2-en-1-yl) piperidine-3-carboxylic acid hydrochloride 258 mg was obtained as a light brown solid.

実施例１０：[2-({2,3-ジクロロ-4-[(1E)-3-オキソプロプ-1-エン-1-イル]フェニル}スルファニル)フェノキシ]酢酸 t-ブチルエステル410 mg、1-アセチルピペラジン155 mg、酢酸0.22 ml及び1,2-ジクロロエタン3 mlの混合物を室温で1時間撹拌した後、NaBH(OAc)3 403 mgを加え、室温で3日間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液3 mlを加え、生成物をクロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥した後、減圧下で濃縮し[2-({4-[(1E)-3-(4-アセチルピペラジン-1-イル)プロプ-1-エン-1-イル]-2,3-ジクロロフェニル}スルファニル)フェノキシ]酢酸 t-ブチルエステルの粗生成物を得た。得られた粗生成物を塩化メチレン5 mlに溶解し、トリフルオロ酢酸2 mlを加えて2時間攪拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝20／1）で精製した後、4M塩化水素／酢酸エチル溶液1 mlを加え、減圧下で濃縮した。得られた残渣をアセトニトリルとメタノールの混合液から再結晶して[2-({4-[(1E)-3-(4-アセチルピペラジン-1-イル)プロプ-1-エン-1-イル]-2,3-ジクロロフェニル}スルファニル)フェノキシ]酢酸 塩酸塩113 mgを無色結晶として得た。
実施例１１：1-アセチル-4-(3-{2,3-ジクロロ-4-[(3-メトキシフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン670 mgの塩化メチレン10 ml溶液に-78℃にて、1M三臭化ホウ素／塩化メチレン溶液3.27 mlを滴下し、室温にて16時間撹拌した。常法による処理を行った後、シリカゲルカラムクロマトグラフィー（メタノール／クロロホルム＝3／97〜7／93）で精製した。得られた固体を酢酸エチル2 mlに溶解し、4M塩化水素／酢酸エチル溶液1 mlを加えた後、溶媒を留去した。得られた残渣をエタノールと酢酸エチルの混合液から再結晶して、3-({4-[(1E)-3-(4-アセチルピペラジン-1-イル)プロプ-1-エン-1-イル]-2,3-ジクロロフェニル}スルファニル)フェノール 塩酸塩123 mgを無色結晶として得た。
実施例１２：2-({4-[(1E)-3-(4-アセチルピペラジン-1-イル)プロプ-1-エン-1-イル]-2,3-ジクロロフェニル}スルファニル)フェノール236 mgのDMF2 ml溶液に、1,3-ジオキソラン-2-オン106 mgを加え、100℃で14時間撹拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（トリエチルアミン／メタノール／クロロホルム＝1／10／200）で精製した後、4M塩化水素／酢酸エチル溶液１mlを加え、減圧下で濃縮した。得られた残渣を酢酸エチルとエタノールの混合液から再結晶して2-[2-({4-[(1E)-3-(4-アセチルピぺラジン-1-イル)プロプ-1-エン-1-イル]-2,3-ジクロロフェニル}スルファニル)フェノキシ]エタノール 塩酸塩126 mgを無色結晶として得た。 Example 10: [2-({2,3-dichloro-4-[(1E) -3-oxoprop-1-en-1-yl] phenyl} sulfanyl) phenoxy] acetic acid t-butyl ester 410 mg, 1- A mixture of 155 mg of acetylpiperazine, 0.22 ml of acetic acid and 3 ml of 1,2-dichloroethane was stirred at room temperature for 1 hour, and then NaBH (OAc) 3 403 mg was added and stirred at room temperature for 3 days. To the reaction solution was added 3 ml of saturated aqueous sodium hydrogen carbonate solution, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure [2-({4-[(1E) -3- (4-acetylpiperazin-1-yl) prop-1-en-1-yl] A crude product of -2,3-dichlorophenyl} sulfanyl) phenoxy] acetic acid t-butyl ester was obtained. The obtained crude product was dissolved in 5 ml of methylene chloride, 2 ml of trifluoroacetic acid was added, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 20/1), and then added with 1 ml of 4M hydrogen chloride / ethyl acetate solution, and concentrated under reduced pressure. The resulting residue was recrystallized from a mixture of acetonitrile and methanol to give [2-({4-[(1E) -3- (4-acetylpiperazin-1-yl) prop-1-en-1-yl] 113 mg of -2,3-dichlorophenyl} sulfanyl) phenoxy] acetic acid hydrochloride was obtained as colorless crystals.
Example 11: 1-acetyl-4- (3- {2,3-dichloro-4-[(3-methoxyphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperazine 670 mg methylene chloride 10 To the ml solution, 3.27 ml of 1M boron tribromide / methylene chloride solution was added dropwise at −78 ° C., followed by stirring at room temperature for 16 hours. After carrying out a conventional treatment, the product was purified by silica gel column chromatography (methanol / chloroform = 3/97 to 7/93). The obtained solid was dissolved in 2 ml of ethyl acetate, 1 ml of 4M hydrogen chloride / ethyl acetate solution was added, and then the solvent was distilled off. The resulting residue was recrystallized from a mixture of ethanol and ethyl acetate to give 3-({4-[(1E) -3- (4-acetylpiperazin-1-yl) prop-1-en-1-yl ] -2,3-Dichlorophenyl} sulfanyl) phenol hydrochloride 123 mg was obtained as colorless crystals.
Example 12: 2-({4-[(1E) -3- (4-acetylpiperazin-1-yl) prop-1-en-1-yl] -2,3-dichlorophenyl} sulfanyl) phenol 236 mg 106 mg of 1,3-dioxolan-2-one was added to 2 ml of DMF, and the mixture was stirred at 100 ° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (triethylamine / methanol / chloroform = 1/10/200), and then added with 1 ml of 4M hydrogen chloride / ethyl acetate solution, and reduced pressure. Concentrated. The obtained residue was recrystallized from a mixture of ethyl acetate and ethanol to give 2- [2-({4-[(1E) -3- (4-acetylpiperazin-1-yl) prop-1-ene- 1-yl] -2,3-dichlorophenyl} sulfanyl) phenoxy] ethanol hydrochloride 126 mg was obtained as colorless crystals.

実施例１３：t-ブチル 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジル ピペラジン-1,4-ジカルボキシラート1.0 gのジオキサン5 ml溶液に、4M塩化水素／酢酸エチル溶液を1 ml加え、室温で5時間撹拌した後減圧下で濃縮し、ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル 塩酸塩700 mgを無色非晶性固体として得た。
実施例１４：1-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン 二塩酸塩237 mg、グリコール酸41 mg、DMF 4 mlの混合物に、トリエチルアミン134 μl、WSC・HCl 102 mg、HOBt 72 mgを加え、室温で一晩攪拌した。常法による処理を行った後、シリカゲルカラムクロマトグラフィー（クロロホルム〜メタノール／クロロホルム＝1／99）で精製した後、酢酸エチルに溶解して4M塩化水素／酢酸エチル溶液を加え、減圧下で濃縮した。得られた残渣をアセトニトリルとメタノールの混合液から再結晶して、2-[4-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン-1-イル]-2-オキソエタノール 塩酸塩113 mgを無色結晶として得た。
実施例１５：4-{2-[(t-ブトキシカルボニル)アミノ]エチル}ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル138 mgの塩化メチレン2 ml溶液に、氷冷下トリフルオロ酢酸0.5 mlを加え、30分間攪拌した。減圧下濃縮して得られた残渣をピリジン2 mlに溶解し、氷冷下無水酢酸0.28 mlを加えた。室温で1時間攪拌した後水を加え、酢酸エチルで抽出し、有機層を1M塩酸と飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム＝1／99〜1／10）で精製した後、4M塩化水素／酢酸エチル溶液１mlを加え、減圧下で濃縮した。得られた残渣を酢酸エチルとメタノールの混合液から再結晶して、4-[2-(アセチルアミノ)エチル]ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル 塩酸塩40 mgを無色結晶として得た。 Example 13: t-Butyl 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl piperazine-1,4-dicarboxylate 1.0 g in 5 ml dioxane in 4 M hydrogen chloride / ethyl acetate solution 1 ml of the reaction mixture was stirred at room temperature for 5 hours, and concentrated under reduced pressure to give 700 mg of piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester hydrochloride as colorless Obtained as a crystalline solid.
Example 14: 1-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperazine 237 mg, To a mixture of 41 mg of glycolic acid and 4 ml of DMF were added 134 μl of triethylamine, 102 mg of WSC · HCl, 72 mg of HOBt, and the mixture was stirred overnight at room temperature. After treatment by a conventional method, the product was purified by silica gel column chromatography (chloroform to methanol / chloroform = 1/99), dissolved in ethyl acetate, added with 4M hydrogen chloride / ethyl acetate solution, and concentrated under reduced pressure. . The obtained residue was recrystallized from a mixture of acetonitrile and methanol to give 2- [4-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop. 113 mg of -2-en-1-yl) piperazin-1-yl] -2-oxoethanol hydrochloride was obtained as colorless crystals.
Example 15: 4- {2-[(t-butoxycarbonyl) amino] ethyl} piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester 138 mg of methylene chloride To the 2 ml solution, 0.5 ml of trifluoroacetic acid was added under ice cooling and stirred for 30 minutes. The residue obtained by concentration under reduced pressure was dissolved in 2 ml of pyridine, and 0.28 ml of acetic anhydride was added under ice cooling. After stirring at room temperature for 1 hour, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (methanol / chloroform = 1/99 to 1/10), and then added with 1 ml of 4M hydrogen chloride / ethyl acetate solution and concentrated under reduced pressure. did. The resulting residue was recrystallized from a mixture of ethyl acetate and methanol to give 4- [2- (acetylamino) ethyl] piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) Sulfanyl] benzyl ester hydrochloride 40 mg was obtained as colorless crystals.

実施例１６：ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル 塩酸塩150 mgの塩化メチレン5 ml溶液に、トリエチルアミン0.07 ml、アセトキシ酢酸クロリド55 mgの順で加え、室温で12時間撹拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝4／1〜2／1）で精製することにより4-[(アセトキシ)アセチル]ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル109 mgを無色非晶性固体として得た。
実施例１７：ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル 塩酸塩100 mgの塩化メチレン5 ml溶液に、トリエチルアミン0.07 ml、メタンスルホン酸クロリド0.045 mlの順で加え、室温で11時間撹拌した。反応液を減圧下で濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２／１）で精製することにより4-(メタンスルホニル)ピペラジン-１-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル81 mgを無色非晶性固体として得た。
実施例１８：4-{[(4S)-2,2-ジメチル-1,3-ジオキソラン-4-イル]カルボニル}ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル112 mgのメタノール2 ml溶液に、4M塩化水素／酢酸エチル溶液を0.1 ml加え、室温で2時間撹拌した後減圧下で濃縮し、4-[(2S)-2,3-ジヒドロキシプロパノイル]ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステル105 mgを無色非晶性固体として得た。 Example 16: Piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester To a solution of 150 mg of hydrochloride in 5 ml of methylene chloride, 0.07 ml of triethylamine and 55 mg of acetoxyacetate chloride Were added in this order, followed by stirring at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 to 2/1) to give 4-[(acetoxy) acetyl] piperazine-1-carboxylic acid. 109 mg of the acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester was obtained as a colorless amorphous solid.
Example 17: Piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester To a solution of 100 mg of hydrochloride in 5 ml of methylene chloride, 0.07 ml of triethylamine and 0.045 of methanesulfonic acid chloride The solution was added in the order of ml and stirred at room temperature for 11 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 4- (methanesulfonyl) piperazine-1-carboxylic acid 2,3-dichloro 81 mg of -4-[(2-isopropylphenyl) sulfanyl] benzyl ester was obtained as a colorless amorphous solid.
Example 18: 4-{[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] carbonyl} piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) ) Sulfanyl] benzyl ester 112 mg in a methanol 2 ml solution was added 0.1 ml of 4M hydrogen chloride / ethyl acetate solution, stirred at room temperature for 2 hours, concentrated under reduced pressure, 4-[(2S) -2,3- 105 mg of dihydroxypropanoyl] piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester was obtained as a colorless amorphous solid.

実施例１９：(2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}-1-(1-トリチル-1H-イミダゾール-4-イル)プロプ-2-エン-1-オン1.10gの酢酸60 ml溶液に酸化白金150 mgを加え、水素雰囲気下4気圧で、室温にて4日間攪拌した。減圧下濃縮後、クロロホルムと飽和炭酸水素ナトリウム水溶液を加え、不溶物を濾去してから有機層を分液し、硫酸マグネシウムで乾燥した。減圧下濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製して、3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}-1-(1H-イミダゾール-4-イル)プロパン-1-オン275 mgを淡黄色非晶性固体として得た。
実施例２０：1-アセチル-4-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロプ-2-エン-1-イル)ピペラジン250mgを、メタノール10ml中、濃塩酸0.2ml及び酸化白金64mgの存在下、接触水素還元を行った後、実施例１９と同様の後処理を行った。得られた残渣を４Ｍ塩化水素／酢酸エチル溶液で処理した後、酢酸エチルとエタノールの混合液から再結晶して、1-アセチル-4-((2E)-3-{2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]フェニル}プロピル)ピペラジン 塩酸塩45mgを無色結晶として得た。
実施例２１：4-[2-(アセチルアミノ)エチル]ピペラジン-1-カルボン酸 4-{[2-({[t-ブチル(ジメチル)シリル]オキシ}メチル)フェニル]スルファニル}-2,3-ジクロロベンジルエステル417 mgのTHF10 ml溶液に、フッ化テトラ n-ブチルアンモニウム 三水和物231 mgを加え、室温にて20分間撹拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム＝1／99〜6／94）で精製した後、酢酸エチルに溶解して4M塩化水素／酢酸エチル溶液を加え、減圧下濃縮した。得られた残渣を酢酸エチルとエタノールの混合液から再結晶して、4-[2-(アセチルアミノ)エチル]ピペラジン-1-カルボン酸 2,3-ジクロロ-4-{[2-(ヒドロキシメチル)フェニル]スルファニル}ベンジルエステル170 mgを得た。 Example 19: (2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} -1- (1-trityl-1H-imidazol-4-yl) prop-2- To a solution of en-1-one 1.10 g in 60 ml of acetic acid, 150 mg of platinum oxide was added, followed by stirring at 4 atm under a hydrogen atmosphere at room temperature for 4 days. After concentration under reduced pressure, chloroform and saturated aqueous sodium hydrogen carbonate solution were added, the insoluble material was filtered off, the organic layer was separated, and dried over magnesium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (ethyl acetate) to give 3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} -1- (1H -Imidazol-4-yl) propan-1-one 275 mg was obtained as a pale yellow amorphous solid.
Example 20: 250 mg of 1-acetyl-4-((2E) -3- {2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] phenyl} prop-2-en-1-yl) piperazine After performing catalytic hydrogen reduction in the presence of 0.2 ml of concentrated hydrochloric acid and 64 mg of platinum oxide in 10 ml of methanol, the same post treatment as in Example 19 was carried out. The obtained residue was treated with a 4M hydrogen chloride / ethyl acetate solution and then recrystallized from a mixture of ethyl acetate and ethanol to give 1-acetyl-4-((2E) -3- {2,3-dichloro- 45 mg of 4-[(2-isopropylphenyl) sulfanyl] phenyl} propyl) piperazine hydrochloride was obtained as colorless crystals.
Example 21: 4- [2- (acetylamino) ethyl] piperazine-1-carboxylic acid 4-{[2-({[t-butyl (dimethyl) silyl] oxy} methyl) phenyl] sulfanyl} -2,3 -To a solution of 417 mg of dichlorobenzyl ester in 10 ml of THF, 231 mg of tetra n-butylammonium fluoride trihydrate was added and stirred at room temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (methanol / chloroform = 1/99 to 6/94), then dissolved in ethyl acetate and added with 4M hydrogen chloride / ethyl acetate solution. And concentrated under reduced pressure. The obtained residue was recrystallized from a mixture of ethyl acetate and ethanol to give 4- [2- (acetylamino) ethyl] piperazine-1-carboxylic acid 2,3-dichloro-4-{[2- (hydroxymethyl ) Phenyl] sulfanyl} benzyl ester 170 mg was obtained.

実施例２２：4-(2-ヒドロキシエチル)ピペラジン-1-カルボン酸 2,3-ジクロロ-4-[(2-ホルミルフェニル)スルファニル]ベンジルエステル300 mgのDMF2 ml溶液に、ホスホノ酢酸トリエチル180 mg、炭酸カリウム140 mgを加え、室温で11時間撹拌した。常法による処理を行った後、シリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝20／1）で精製し、4M塩化水素／酢酸エチル溶液1 mlを加え、減圧下で濃縮し4-(2-ヒドロキシエチル)ピペラジン-1-カルボン酸 2,3-ジクロロ-4-({2-[(1E)-3-エトキシ-3-オキソプロプ-1-エン-1-イル]フェニル}スルファニル)ベンジルエステル 塩酸塩205 mgを無色非晶性固体として得た。
実施例２３：4-オキソピペリジン-1-カルボン酸 2,3-ジクロロ-4-[(2-イソプロピルフェニル)スルファニル]ベンジルエステルとN-(2-アミノエチル)アセタミドを原料として、実施例1と同様にして実施例２３の化合物を製造した。 Example 22: 4- (2-hydroxyethyl) piperazine-1-carboxylic acid 2,3-dichloro-4-[(2-formylphenyl) sulfanyl] benzyl ester 300 mg in DMF 2 ml solution, phosphonoacetic acid triethyl 180 mg Then, 140 mg of potassium carbonate was added, and the mixture was stirred at room temperature for 11 hours. After the usual treatment, purify by silica gel column chromatography (chloroform / methanol = 20/1), add 1 ml of 4M hydrogen chloride / ethyl acetate solution, concentrate under reduced pressure, and add 4- (2-hydroxyethyl). ) Piperazine-1-carboxylic acid 2,3-dichloro-4-({2-[(1E) -3-ethoxy-3-oxoprop-1-en-1-yl] phenyl} sulfanyl) benzyl ester hydrochloride 205 mg Was obtained as a colorless amorphous solid.
Example 23: 4-oxopiperidine-1-carboxylic acid 2,3-dichloro-4-[(2-isopropylphenyl) sulfanyl] benzyl ester and N- (2-aminoethyl) acetamide as raw materials In the same manner, the compound of Example 23 was produced.

以上の実施例と同様にして実施例２４〜２００の化合物を製造した。それらの構造式と物理化学的性状を、後記表１２〜表２９に示す。又、後記表３０〜表３３の化合物は前記実施例や製造法に記載の方法とほぼ同様にして、或いはそれらの方法より当業者に自明な若干の変法を適用することにより、容易に製造することができる。   The compounds of Examples 24-200 were produced in the same manner as in the above Examples. Their structural formulas and physicochemical properties are shown in Tables 12 to 29 below. Further, the compounds shown in Tables 30 to 33 described below can be easily produced by substantially the same methods as those described in the above examples and production methods, or by applying some variations obvious to those skilled in the art from those methods. can do.

なお、表中の記号は以下の意味を有する。置換基の前の数字は置換位置を示し、数字が複数個あるものは複数の置換を示す。例えば、2,3-Cl2は2,3-ジクロロを示す。但し、3,4-O(CH2)2O-は3位及び4位で架橋したエチレンジオキシ基を示す。
Me：メチル、Et：エチル、iPr：イソプロピル、tBu：t-ブチル、Ac：アセチル、TBS：t-ブチルジメチルシリル、Boc：t-ブトキシカルボニル、REx：参考例番号、Ex：実施例番号、Cmp：化合物番号、Syn：製造法（数字は同様に製造した実施例番号を示す。）、Sal：塩（無記載：フリー体；HCl：塩酸塩；Oxa：シュウ酸塩；数字は酸成分のモル比を示し、例えば、2HClは二塩酸塩を意味する。）、Dat：物理化学的性状（FP：FAB-MS(M+H)+、FN：FAB-MS(M-H)-、EI：EI-MS(M)+、ESI：ESI-MS(M+H)+）、EA：元素分析値(%)（Cal：計算値；Fnd：実測値）、NMR1：核磁気共鳴スペクトル（DMSO-d6, TMS内部標準）の代表的なピークのδ値、NMR2：核磁気共鳴スペクトル（CDCl3, TMS内部標準）の代表的なピークのδ値）。 The symbols in the table have the following meanings. The number before the substituent indicates the substitution position, and a plurality of numbers indicates a plurality of substitutions. For example, 2,3-Cl 2 represents 2,3-dichloro. However, 3,4-O (CH 2 ) 2 O— represents an ethylenedioxy group crosslinked at the 3-position and 4-position.
Me: methyl, Et: ethyl, iPr: isopropyl, tBu: t-butyl, Ac: acetyl, TBS: t-butyldimethylsilyl, Boc: t-butoxycarbonyl, REx: reference example number, Ex: example number, Cmp : Compound number, Syn: Production method (numbers indicate the numbers of the examples produced in the same manner), Sal: salt (no description: free form; HCl: hydrochloride salt; Oxa: oxalate salt; numbers are moles of acid component) For example, 2HCl means dihydrochloride), Dat: physicochemical properties (FP: FAB-MS (M + H) + , FN: FAB-MS (MH) − , EI: EI− MS (M) + , ESI: ESI-MS (M + H) + ), EA: elemental analysis value (%) (Cal: calculated value; Fnd: measured value), NMR1: nuclear magnetic resonance spectrum (DMSO-d 6 , TMS internal standard) representative peak δ value, NMR2: nuclear magnetic resonance spectrum (CDCl 3 , TMS internal standard representative peak δ value).

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Claims (2)

下記式（Ｉ）で示されるスルフィド誘導体又はその製薬学的に許容される塩。
Figure 2007186422
 A：アリール又はヘテロ環基；
R1：同一又は互いに異なって、-H、-R0、ハロゲン、-OH、-O-R0、-O-CO-NR4-R0、-NH2、-NO2、-NR4-R0、-S-R0、-SO-R0、-SO2-R0、-CO-R0、-CHO、-CN、-CO-NH2、-CO-NR4-R0、-CO2H、-CO2-R0、-CO-NH-OH、-SO3H、-SO2-NH2、-SO2-NR4-R0、-NR4-CO-R0、-NR4-SO2-R0、置換されていてもよいシクロアルキル、-低級アルケニレン-CO2-R0、-低級アルケニレン-CO2H、-低級アルケニレン-CO-NH2、-低級アルケニレン-CO-NR4-R0、-低級アルケニレン-CO-置換されていてもよいヘテロ環、置換されていてもよいヘテロ環、-CO-置換されてもよいヘテロ環、-O-置換されてもよいヘテロ環、-NR4-置換されてもよいヘテロ環、-NR4-CO-置換されてもよいヘテロ環、-CO-NR4-置換されてもよいヘテロ環、-S-置換されてもよいヘテロ環、-NR4-SO2-置換されてもよいヘテロ環、置換されていてもよいアリール、-CO-置換されてもよいアリール、-O-置換されてもよいアリール、-NR4-置換されてもよいアリール、-NR4-CO-置換されてもよいアリール、-CO-NR4-置換されてもよいアリール、-S-置換されてもよいアリール又は-NR4-SO2-置換されてもよいアリール；
R0：同一若しくは互いに異なって、置換されていてもよい低級アルキル；
R4：同一若しくは互いに異なって、-H又は置換されていてもよい低級アルキル；
R00：同一若しくは互いに異なって、-OH又は-O-低級アルキルで置換されていてもよい低級アルキレン；
n：1、2又は3；
R2及びR3：同一又は互いに異なって、-H、-R0、ハロゲン、-CN、-NO2、-O-R0、-S-R0、-SO-R0又は-SO2-R0、但しR2及びR3が同時に-Hではない；
X：-R00-、低級アルケニレン、-R00-O-CO-、-R00-O-CO-NR4-、-R00-O-CO-NR4-R00-、-R00-CO-、低級アルケニレン-NR4-、低級アルケニレン-NR4-R00-又は低級アルケニレン-NR4-CO-；
B：置換されていてもよいアリール、置換されていてもよいシクロアルキル、又は置換されていてもよいヘテロ環基；
Y：単結合、-R00-、-CO-R00-、-NR4-R00-、-O-R00-、-CO2-R00-、-CO-NR4-R00-、-NR4-CO-R00-又は-R00-O-R00-；及び
Z：-H、-R0、-CO2H、-CO-NH2、-CO2-R0、-CHO、-CO-NH-OH、-C(NH)-NH2、-SO3H、-SO2-R0、-SO2-NH2、-SO2-NR4-R0 、-PO(OR4)2、-O-PO(OR4)2、-CN、-OH、-O-R0、-NH2、-NR4-R0、-NH-C(NH)-NH2、-NR4-CO-R0、-NR4-SO2-R0、-NR4-CO-NH2、-NR4-CO-NR4-R0、-NR4-CO-NR4-R0、-NR4-SO2-NH2、-O-CO-NR4-R0、-CO-NR4-R0、-CO-R0、-O-CO-R0、-CO-CO2H、置換されていてもよいヘテロ環、置換されていてもよいアリール、置換されていてもよいシクロアルキル、-CO-置換されていてもよいヘテロ環、-CO-置換されていてもよいアリール、-CO-NR4-置換されていてもよいヘテロ環、-CO-NR4-置換されていてもよいアリール、-CO-O-置換されていてもよいヘテロ環、-SO2-置換されていてもよいヘテロ環、-O-CO-置換されていてもよいヘテロ環、-O-置換されていてもよいヘテロ環、-NR4-置換されていてもよいヘテロ環、-NR4-CO-置換されていてもよいヘテロ環、-NR4-SO2-置換されていてもよいヘテロ環及び-SO2-NR4-置換されていてもよいヘテロ環。） A sulfide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.
Figure 2007186422
 A: an aryl or heterocyclic group;
R 1 : same or different, —H, —R 0 , halogen, —OH, —OR 0 , —O—CO—NR 4 —R 0 , —NH 2 , —NO 2 , —NR 4 —R 0 , -SR 0 , -SO-R 0 , -SO 2 -R 0 , -CO-R 0 , -CHO, -CN, -CO-NH 2 , -CO-NR 4 -R 0 , -CO 2 H, -CO 2 -R 0 , -CO-NH-OH, -SO 3 H, -SO 2 -NH 2 , -SO 2 -NR 4 -R 0 , -NR 4 -CO-R 0 , -NR 4 -SO 2 -R 0, optionally substituted cycloalkyl, - lower alkenylene -CO 2 -R 0, - lower alkenylene -CO 2 H, - lower alkenylene -CO-NH 2, - lower alkenylene -CO-NR 4 - R 0 , -lower alkenylene-CO-optionally substituted heterocycle, optionally substituted heterocycle, -CO-optionally substituted heterocycle, -O-optionally substituted heterocycle,- NR 4 -optionally substituted heterocycle, -NR 4 -CO-optionally substituted heterocycle, -CO-NR 4 -optionally substituted heterocycle, -S-optionally substituted heterocycle, -NR 4 -SO 2 -optionally substituted heterocycle, substituted Is aryl which may have, -CO- optionally substituted aryl, -O- optionally substituted aryl, -NR 4 - optionally substituted aryl, which may be -NR 4 -CO- substituted aryl , -CO-NR 4 - optionally substituted aryl, -S- optionally substituted aryl or -NR be 4 -SO 2 - optionally substituted aryl;
R 0 : the same or different from each other and optionally substituted lower alkyl;
R 4 : the same or different from each other, —H or optionally substituted lower alkyl;
R 00 : lower alkylene which may be the same or different and may be substituted with —OH or —O-lower alkyl;
n: 1, 2 or 3;
R 2 and R 3 are the same or different from each other, -H, -R 0 , halogen, -CN, -NO 2 , -OR 0 , -SR 0 , -SO-R 0 or -SO 2 -R 0 , R 2 and R 3 are not simultaneously -H;
X: -R 00 -, lower alkenylene, -R 00 -O-CO -, - R 00 -O-CO-NR 4 -, - R 00 -O-CO-NR 4 -R 00 -, - R 00 - CO-, lower alkenylene -NR 4 -, lower alkenylene -NR 4 -R 00 - or lower alkenylene -NR 4 -CO-;
B: aryl which may be substituted, cycloalkyl which may be substituted, or heterocyclic group which may be substituted;
Y: Single bond, -R 00- , -CO-R 00- , -NR 4 -R 00- , -OR 00- , -CO 2 -R 00- , -CO-NR 4 -R 00- , -NR 4 -CO-R 00 -or -R 00 -OR 00- ; and
Z: -H, -R 0 , -CO 2 H, -CO-NH 2 , -CO 2 -R 0 , -CHO, -CO-NH-OH, -C (NH) -NH 2 , -SO 3 H , -SO 2 -R 0 , -SO 2 -NH 2 , -SO 2 -NR 4 -R 0 , -PO (OR 4 ) 2, -O-PO (OR 4 ) 2 , -CN, -OH,- OR 0 , -NH 2 , -NR 4 -R 0 , -NH-C (NH) -NH 2 , -NR 4 -CO-R 0 , -NR 4 -SO 2 -R 0 , -NR 4 -CO- NH 2 , -NR 4 -CO-NR 4 -R 0 , -NR 4 -CO-NR 4 -R 0 , -NR 4 -SO 2 -NH 2 , -O-CO-NR 4 -R 0 , -CO -NR 4 -R 0 , -CO-R 0 , -O-CO-R 0 , -CO-CO 2 H, optionally substituted heterocycle, optionally substituted aryl, optionally substituted Good cycloalkyl, -CO-optionally substituted heterocycle, -CO-optionally substituted aryl, -CO-NR 4 -optionally substituted heterocycle, -CO-NR 4 -substituted Optionally substituted aryl, —CO—O—optionally substituted heterocycle, —SO 2 —optionally substituted heterocycle, —O—CO—optionally substituted heterocycle, —O— heterocycle which may be substituted, -NR 4 - Conversion which may be heterocyclic, -NR 4 -CO- optionally substituted heterocycle, -NR 4 -SO 2 - optionally substituted heterocyclic and -SO 2 -NR 4 - substituted An optional heterocycle. ) Xが低級アルケニレン、-R00-O-CO-、-R00-O-CO-NR4-又は-R00-O-CO-NR4-R00-；
R1が同一又は互いに異なって、-H、-R0、ハロゲン、-O-R0、-NR4-CO-R0、置換されていてもよいヘテロ環、又は-R00-置換されていてもよいヘテロ環；
R2及びR3が同一又は互いに異なって、-H、低級アルキル、ハロゲン、-CN、-NO2又はハロゲンで置換された低級アルキル、但しR2及びR3が同時に-Hではない；及び
Bがフェニレン、テトラヒドロピランジイル又は下式(i)〜(iv)から選択される基
Figure 2007186422
 （ここにk：0、1又は2；
ｑ：0、1又は2；
m：1又は2；
R5及びR6：同一又は互いに異なって、-H又は低級アルキル、或いはR5及びR6が一体となってオキソ基を形成してもよく、或いはR5及びR6が一体となってヘテロ原子で中断されていてもよい低級アルキレンとして、Ｂが架橋環又はスピロ環を形成してもよい）；
である、請求項１記載のスルフィド誘導体又はその製薬学的に許容される塩。 X is a lower alkenylene, -R 00 -O-CO -, - R 00 -O-CO-NR 4 - or -R 00 -O-CO-NR 4 -R 00 -;
R 1 is the same or different from each other, and is —H, —R 0 , halogen, —OR 0 , —NR 4 —CO—R 0 , an optionally substituted heterocycle, or —R 00 —substituted A good heterocycle;
R 2 and R 3 are the same or different from each other and are —H, lower alkyl, halogen, —CN, —NO 2 or lower alkyl substituted with halogen, provided that R 2 and R 3 are not simultaneously —H; and
B is phenylene, tetrahydropyrandiyl or a group selected from the following formulas (i) to (iv)
Figure 2007186422
 (Where k: 0, 1 or 2;
q: 0, 1 or 2;
m: 1 or 2;
R 5 and R 6 are the same or different from each other, —H or lower alkyl, or R 5 and R 6 may be combined to form an oxo group, or R 5 and R 6 are combined to form a hetero As lower alkylene, optionally interrupted by atoms, B may form a bridged or spiro ring);
The sulfide derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
JP2004019666A 2004-01-28 2004-01-28 Arylsulfide derivative Pending JP2007186422A (en)

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